- Email: [email protected]
Amyloid β-interacting partners in Alzheimer's disease: From accomplices to possible therapeutic targets
Accepted Manuscript Title: Amyloid -interacting partners in Alzheimer’s disease: From accomplices to possible therapeutic targets Author: Sun-Ho Han Ph.D. Jong-Chan Park B.S. Inhee Mook-Jung Ph.D. PII: DOI: Reference:
S0301-0082(15)30036-8 http://dx.doi.org/doi:10.1016/j.pneurobio.2015.12.004 PRONEU 1410
To appear in:
Progress in Neurobiology
Received date: Revised date: Accepted date:
25-6-2015 2-12-2015 9-12-2015
Please cite this article as: Han, S.-H., Park, J.-C., Mook-Jung, I.,Amyloid rmbeta-interacting partners in Alzheimer’s disease: From accomplices to possible therapeutic targets, Progress in Neurobiology (2015), http://dx.doi.org/10.1016/j.pneurobio.2015.12.004 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Amyloid -interacting partners in Alzheimer’s disease:
ip t
From accomplices to possible therapeutic targets
cr
us
Sun-Ho Han (Ph.D.), Jong-Chan Park (B.S.) and Inhee Mook-Jung (Ph.D.)*
an
Department of Biochemistry and Biomedical Sciences, Seoul National University,
M
College of Medicine, 28 Yungun-dong, Jongro-gu, Seoul 110-799, Korea
d
Ac ce pt e
*Corresponding Author:
Inhee Mook-Jung, Ph.D
Department of Biochemistry and Biomedical Sciences, Seoul National University, College of Medicine, 28 Yungun-dong, Jongro-gu, Seoul 110-799, Korea E-mail: [email protected]
Phone number: +82-2-740-8245 Fax number: +82-2-3672-7352
Total word count: 12,134
Page 1 of 68
Contents 1. Introduction 2. A-interacting proteins in the blood and brain
2.2. Apolipoprotein E
cr
2.3. A-interacting proteins in the cerebrospinal fluid 2.4. A-interacting proteins in the blood
us
3. Metal ions
ip t
2.1. Albumin
3.1 Copper
an
3.2 Zinc
M
3.3 Iron 3.4 Aluminium
d
3.5 Therapeutic strategy targeting metal ions
Ac ce pt e
4. A-binding membrane components (receptors) 4.1 Receptor for advanced glycation end products 4.2 Low-density lipoprotein-related protein 4.3 Prion protein
4.5 Ephrin type-B receptor2 4.6 Serpin-enzyme complex 4.7 Insulin receptor
4.8 Neurotransmitter receptors 4.9 Integrin 4.10 Leukocyte immunoglobulin-like receptor B2 4.11 Membrane lipids 4.12 Amyloid precursor protein
Page 2 of 68
5. Intracellular A-binding proteins 5.1 Endoplasmic reticulum-associated A-interacting proteins 5.2 Chaperone proteins
ip t
5.3 X11-llike, ˞B-crystallin and lysozyme 6. Mitochondrial A-binding components
cr
6.1 Cytochrome c oxidase
6.3 Mitochondrial permeability transition pore
us
6.2 A-binding alcohol dehydrogenase
an
7. 6.4 Mitochondrial enzymesA-interacting mediators of immune activation 7.1 Toll-like receptors
M
7.2 Receptor for advanced glycation end products
7.4 Microglial receptors
d
7.3 CD36
Ac ce pt e
8. Other amyloidogenic proteins 8.1 alpha-Synuclein 8.2 A40 and 42
8.3 Trnasthyretin
9. Conclusion
Acknowledgements References
Page 3 of 68
Abstract Alzheimer’s disease (AD) is one of the most devastating neurodegenerative diseases in modern society because of insurmountable difficulties in early diagnosis and lack of therapeutic treatments. AD pathogenesis is tightly linked to the abnormal accumulation and
ip t
aggregation of amyloid (A), seemingly the main causative factor of AD; however,
cr
intensive research on A has not yet explained the complexity of AD pathogenesis. Consequently, the role of other supportive partners of A have been elucidated and evaluated
us
in the etiology of AD, and their potential molecular mechanisms have emerged as possible therapeutic targets. In this review, we compile information regarding A-interacting partners
an
in normal conditions and AD pathology, and analyze their etiological roles in diverse areas.
M
Furthermore, we integrate this information into suggestions for probable clinical applications for AD diagnosis and therapeutics. We include A-interacting partners localized to the cell
d
surface and intracellular and extracellular compartments of different cell types ranging from
Ac ce pt e
the central nervous system to peripheral regions. Additionally, we expand the range of Ainteracting partners by including not only proteins, but also inorganic substances like metals, expecting that one of these partners may yield a critical breakthrough in the field of AD diagnostics and therapeutic drug development.
Key Words: Alzheimer’s disease, Amyloid , Amyloid -interacting protein, Blood brain barrier, cerebrospinal fluid
Page 4 of 68
1. Introduction Alzheimer’s disease (AD) is one of the most concerning neurodegenerative diseases in present society due to the lack of early diagnostic methods and therapeutic remedies. Amyloid β (A) plaques are regarded as the main etiological hallmark of AD. Plaque
ip t
formation begins with abnormal production or impaired clearance of A and consequent
cr
accumulation and aggregation, leading to formation of A plaques in the brain (Mawuenyega et al., 2010; Querfurth and LaFerla, 2010). Increased A levels are tightly associated with
us
synaptic dysfunctions and neuronal network perturbations, which are regarded as the main
an
cause of cognitive impairment in AD (Palop and Mucke, 2010). Contrary to AD, in other types of dementia aggregated forms of A are not present, suggesting that aggregation of Aβ
M
peptides is a peculiar characteristic of AD, and plays a pivotal role in its pathogenesis. Therefore, inhibition of A aggregation or its effects may be a key solution to prevent the
d
initiation of AD or slow down its etiological progression.
Ac ce pt e
Accumulating evidence suggests that A elicits its deleterious effects, including toxicity on cellular and synaptic functions, through binding to certain molecular partners. However, other molecules may interact with A and prevent the A-mediated toxic effects. Therefore, Ainteracting proteins and molecules are tightly associated with diverse aspects of AD pathophysiology. Firstly, numerous A-interacting proteins play a critical role in influencing the lifespan of A via regulating A generation, aggregation, disaggregation, and degradation (Bohrmann et al., 1999; Clinton et al., 2010; Hone et al., 2003). Certain A-interacting proteins are capable of modulating the amyloidogenic and catabolic process by interacting with A (Fagan et al., 2002; Ono et al., 2012). Other A-interacting proteins either enhance or inhibit A aggregation by maintaining A in a free or bound form, respectively (Clinton et al., 2010; Schwarzman and Goldgaber, 1996). This process is critical in AD pathogenesis, because abnormally accumulated A, usually the free form of A, aggregates to form
Page 5 of 68
neurotoxic A, whereas bound forms do not tend to aggregate (Bohrmann et al., 1999). Secondly, A-interacting partners, localized in both intra/extracellular compartments and on the cell surface, typically serve as mediators for A-triggered signaling (activation or inhibition) (Freir et al., 2011; Sturchler et al., 2008), which is closely linked to synaptic
ip t
dysfunction and neuronal toxicity. Thirdly, A directly binds to certain enzymes that are
cr
critical in cell dynamics, and modulates their activities and functions (Chen and Yan, 2007; Hernandez-Zimbron et al., 2012; Lustbader et al., 2004), which leads to the breakdown of
us
cellular homeostasis and further toxicity. A-interacting partners attract a great interest, as they might help in understanding the pathophysiology of AD, and therefore, comprehensive
an
assessment of A-interacting proteins and their diverse roles is necessary for developing
M
therapeutic agents for AD targeting these proteins. Careful investigation of A-interacting partners may provide valuable information to understand A-mediated cellular toxicity in AD
Ac ce pt e
these regulatory partners.
d
and promising first-line interventions to delay or prevent disease progression by modulating
2. A-interacting proteins in the blood and brain 2.1 Albumin
Albumin, a 65-kDa protein, is the most abundant protein in the serum, and binds toxic materials in the circulation, including A (Carter and Ho, 1994) (Fig. 1). Serum albumins bind the majority of serum A, sequestrating 90–95% of A in the blood, and therefore, very little free A exists in the blood (Biere et al., 1996; Kuo et al., 2000). In addition, albumin inhibits A polymerization through A/albumin interactions at physiological concentrations; thus, representing 60% of all A polymerization inhibitory activities among various plasma proteins (Bohrmann et al., 1999). Therefore, differences in albumin concentration between the serum (~640 M) and cerebrospinal fluid (CSF, 3 M) might explain why A plaques are
Page 6 of 68
deposited in the brain instead of peripheral tissues (Stanyon and Viles, 2012; Stevens et al., 1979). Level of serum albumin is tightly associated with cognitive impairment, as the elderly with low serum albumin levels have increased odds for impaired cognitive function after adjusting for possible risk factors such as age, sex, and education (Llewellyn et al., 2010).
ip t
Additionally, patients with AD exhibit significantly decreased serum albumin levels
cr
compared with control individuals (Maes et al., 1999), which supports a relationship between serum albumin levels and cognitive impairment. Notably, decreased levels of the albumin/A
us
complex in the serum is associated with an increased prevalence of AD (Yamamoto et al., 2013). Furthermore, a positive correlation between Mini-Mental State Examination (MMSE)
an
scores and decreased serum albumin levels in patients with AD suggests that serum albumin
M
levels are directly correlated with cognitive impairment during AD pathogenesis (Kim et al., 2006). Albumin may act on cognitive function in AD via the inhibition of A fibril growth,
d
which is achieved by both increasing the lag time for A fibrillization and decreasing the
Ac ce pt e
amount of free A, as the formation of amyloid fibers is directly proportional to the amount of the free A (Stanyon and Viles, 2012). Therefore, treatment with human albumin was attempted for patients with mild to moderate AD through plasma exchange to sequestrate free A and modulate the equilibrium between the albumin-bound and free form of A (Boada et al., 2009). Beneficial effects were observed in albumin-treated patients with regard to A40 mobilization and cognitive status scores, including MMSE and the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-Cog); thus, albumin could be a therapeutic target for AD. Additional studies and clinical trials are ongoing to investigate the therapeutic use of albumin and immunoglobulins in the treatment of AD (Costa et al., 2012) (Table 1). 2.2 Apolipoprotein E Apolipoprotein E (ApoE) exists in both the brain and blood. Numerous studies have investigated the binding of ApoE to A and its subsequent involvement in A clearance and
Page 7 of 68
aggregation (Fig. 1). Different ApoE isoforms, either free or lipid-associated forms, produce sodium dodecyl sulfate-resistant complexes with A according to their isoform-specific binding patterns to A (Aleshkov et al., 1997; LaDu et al., 1994; Sanan et al., 1994; Strittmatter et al., 1993b; Yang et al., 1997). ApoE interacts with the residues 12–28 of A,
ip t
and the isoform-specific efficacy for A binding is ApoE2 > ApoE3 > ApoE4 in lipidated
cr
conditions (Strittmatter et al., 1993a; Strittmatter et al., 1993b; Tokuda et al., 2000). This suggests that different binding capacities of various ApoE isoforms may result in different
us
degree of A clearance, which is supported by the increased risk for AD development in
an
ApoE epsilon 4 allele carriers. However, the consequences of ApoE/Aβ interactions are controversial, even though it is obvious that ApoE affects AD pathogenesis by modulating A
M
aggregation and clearance. Some reports suggest that interaction of ApoE and A, regardless of the ApoE isotype, promotes A fibrillization; however, apoE4 exhibits a particularly high
d
efficacy for inducing A fibrillization compared with ApoE2 and ApoE3 (Castano et al., 1995;
Ac ce pt e
Wisniewski et al., 1994). By contrast, other in vitro studies demonstrated that human ApoE isoforms decrease A fibrillization due to the inhibition of A nucleation formation (Webster and Rogers, 1996; Wood et al., 1996).
In vivo studies using mouse models of AD revealed that overexpression of different ApoE isoforms had various effects on AD neuropathogenesis by modulating A deposition and plaque formation (Fagan et al., 2002; Holtzman et al., 2000), and the ApoE4 isoform promotes the most prominent fibrillar A deposition. Besides their role in A deposition, both murine and human ApoE are crucial in regulating neuritic degeneration (Holtzman et al., 2000). Human ApoE isoforms are more beneficial for delaying A deposition than mouse ApoE molecules (Fagan et al., 2002), which is consistent with the finding that apoE levels are decreased in the serum of patients with AD, and this decrease correlates with disease severity as represented by the MMSE score (Han et al., 2014). The beneficial effects of human ApoE
Page 8 of 68
expression are also isoform-dependent, as human ApoE3 expression delayed synaptic deficits, while ApoE4 expression failed to protect against them (Buttini et al., 2002). Furthermore, amyloid plaque deposition was more prominent following ApoE4 expression compared with ApoE3 expression. In other study, ApoE knockout mice exhibit a significant decrease in A
ip t
deposition, neuritic dystrophy, and amyloid plaques (Bales et al., 1997; Holtzman et al., 2000;
cr
Holtzman et al., 1999).
In addition, ApoE is involved in A metabolism, including A production and clearance.
us
Although the isomer-specific involvement of ApoE in amyloid precursor protein (APP) processing remains controversial (Cedazo-Minguez et al., 2001; Ye et al., 2005), it is
an
conceivable that ApoE influences A clearance and metabolism through several mechanisms.
M
The connection between ApoE and A metabolism is supported by the ApoE-mediated decrease of soluble A levels, localization of A in membrane microdomains (Fagan et al.,
d
2002), and AD-related alterations of ApoE levels in the CSF and serum (Gupta et al., 2011;
Ac ce pt e
Han et al., 2014; Hesse et al., 2000). Lipidated ApoE can sequestrate A, and modulate either its cellular degradation by reuptake through receptor-mediated endocytosis or its systemic removal after crossing the blood brain barrier (BBB) (Jiang et al., 2008; Kim et al., 2009; Trouw et al., 2008; Yamauchi et al., 2000). Therefore, diverse ApoE-targeting therapeutic approaches have been attempted recently, such as increasing ApoE levels, increasing ApoE receptor expression, and modulation of ApoE/A interactions. Blocking A/ApoE interaction by non-toxic homologous to the binding motif within ApoE prevents brain A accumulation, neuritic degeneration and ameliorate memory deficit in AD model mice (Pankiewicz et al., 2014). Other study shows that A/ApoE interaction contributes to intraneuronal A accumulation, demonstrating increased A content using neurons/astrocyte co-culture system (Kuszczyk et al., 2013). In this study, blocking A/ApoE interaction using in vitro homologous and in vivo knockout mice inhibit intracellular A accumulation and loss of
Page 9 of 68
synaptic protein, which indicate possible therapy of modulating A/ApoE interaction. Transcriptional activation of ApoE expression by retinoid X receptor (RXR) agonists, most notably bexarotene (Targretin), a highly selective and BBB permeable RXR agonist, increases A clearance and microglial phagocytosis through the activation of peroxisome
ip t
proliferator-activated receptor gamma (PPAR) and liver X receptor (LXR) (Cramer et al.,
cr
2012). In a mouse model of AD, bexarotene reduces A levels in the cerebral interstitial fluid, cortex, and hippocampus; these levels correlate with the behavioral improvements and
us
bexarotene-mediated increases in ApoE expression. This suggests that a treatment targeting ApoE may be beneficial for the treatment of AD. Notably, bexarotene is currently undergoing
an
a phase 2 clinical trial (ClinicalTrials.gov identifier: NCT01782742, Table 1) for the
M
treatment of amyloid plaques in AD (Aicardi, 2013; Dai et al., 2014). However, controversial genetic studies also suggest that decreasing ApoE levels are beneficial in AD, proving
d
decrease A level, plaque formation and microglial activation by genetically manipulated
Ac ce pt e
reduction of ApoE level (Bien-Ly et al., 2012; Kim et al., 2011). Further studies are necessary to validate the function of ApoE in A metabolism in vivo and in vitro, because the effect of ApoE on A clearance is likely affected by diverse conditions including lipidation status, isomer type, inflammatory activation, and BBB integrity during AD pathogenesis. 2.3 A-interacting proteins in the cerebrospinal fluid Apolipoprotein J (apoJ, clusterin) is a sulfated glycoprotein present in most body fluids, and it binds to a diverse spectrum of molecules (Aronow et al., 1993; Calero et al., 2000; de Silva et al., 1990). Among its diverse ligands, ApoJ interacts with soluble A peptides in a 1:1 stoichiometry regardless of its lipidation status, and forms a stable complex under physiological conditions (Calero et al., 2000). This binding between A and apoJ is saturable, reversible, and of high affinity with a dissociation constant of 2ൈ10-9 M, which is not likely to be dissociated by other competitors such as ApoE, transthyretin, or 1-antichymotrypsin
Page 10 of 68
(Matsubara et al., 1995). Formation of the apoJ/A complex prevents the aggregation, polymerization, and fibrillization of A, which was proved by the co-incubation of A and apoJ. apoJ serves as the major A-binding protein in the CSF under normal conditions; however, the A binding propensity of apo proteins shifts during AD pathogenesis from apoJ
ip t
towards ApoE (Golabek et al., 1995). Besides the protective role of apoJ against A
cr
aggregation, apoJ is neuroprotective during cellular stress, and is upregulated to defend neurons against local damage after diverse insults including the pathological progression of
us
AD (Calero et al., 2000). Binding of apoJ and A accelerates the receptor-mediated cellular clearance of A from the brain by facilitating the binding of A to the low-density lipoprotein
an
receptor-related protein (LRP) 2/megalin (Hammad et al., 1997). In addition, apoJ can trigger
M
protective signaling cascades directly, which affect neurodegeneration and apoptosis, or activate the recovery systems regulating lipid transport or membrane recycling (Calero et al.,
d
2000). Furthermore, apoJ is co-localized with A fibrillary deposits and present in amyloid
Ac ce pt e
plaques and cerebrovascular amyloid deposits in the cortex and hippocampus of patients; however, it is not present in neurofibrillary tangles (Calero et al., 2000; McGeer et al., 1992). Increased mRNA and protein expression of apoJ is demonstrated in the hippocampus and cortex of the patients with AD, which implies a compensatory protective response during AD pathogenesis (Duguid et al., 1989; May et al., 1990; Oda et al., 1994). In contrast to the increase in apoJ levels in the AD brain, apoJ levels are decreased in the CSF, which might serve as a useful diagnostic biomarker (Puchades et al., 2003). Other A-binding proteins that exist at low concentrations show a mild reduction in their levels in the CSF during AD pathogenesis, including -trace/prostaglandin D2 synthase, cystatin C, 1-antitrypsin, and transthyretin (Hansson et al., 2009). Among them, reduction of 1-antitrypsin and transthyretin levels is AD-specific, while reduction in levels of the others is also shown in frontotemporal dementia. Positive correlations between the levels of A1-42
Page 11 of 68
and transthyretin, cystatin C, and -trace/prostaglandin D2 synthase in the CSF from AD suggest that deficient A-binding by partner proteins may influences the amyloidogenic pathway during AD pathogenesis (Hansson et al., 2009). 2.4 A-interacting proteins in the blood
ip t
In addition to albumin and ApoE, A interacts with diverse plasma proteins, including
cr
transthyretin, amyloid P component, 1-antichymotrypsin, and 2-macroglobulin (Du et al., 1997; Janciauskiene et al., 1998; Kalaria and Perry, 1993; Schwarzman et al., 1994) (Fig. 1).
us
Transthyretin is a 64-kDa homotetrameric protein synthesized in the choroid plexus; it is present in the CSF and serum(Sousa et al., 2007). Transthyretin binds and sequestrates A,
an
and subsequently inhibits Aβ aggregation and fibrillation in vitro (Schwarzman and
M
Goldgaber, 1996). The A binding domains of transthyretin were recently identified; strong binding is associated with residues 106–117 (strand G on the inner -sheet of transthyretin)
d
and a weak interaction at residues 59–83 (strand E through the E/F helix and loop) (Du et al.,
Ac ce pt e
2012). In another study, transthyretin was demonstrated to interact with, cleave, and degrade A aggregates (Costa et al., 2008). Furthermore, transthyretin levels in the CSF, serum, and plasma were altered significantly in the patients with AD, and the extent of decrease in plasma transthyretin levels correlates with the severity of AD pathology (Castano et al., 2006; Han et al., 2011a; Hansson et al., 2009; Velayudhan et al., 2012). Accordingly, increased transthyretin expression was suggested as one of the protective mechanisms against AD progression, because it might prevent plaque deposition and A-mediated neuronal toxicity in the brains of mice overexpressing APP with Swedish mutation (Stein and Johnson, 2002). These results indicate that transthyretin may have beneficial effects in both a diagnosis and therapeutic strategy in AD. Similar to transthyretin, 2-macroglobulin interacts with A, and prevents A fibril formation (Hughes et al., 1998). 2-Macroglobulin is the specific ligand for LRP, and promotes A
Page 12 of 68
clearance through LRP in cortical neurons (Chappell et al., 1992; Qiu et al., 1999). Interaction of A with 2-macroglobulin protease complexes increases A degradation, which may reduce the risk of AD development (Lauer et al., 2001). Notably, 2macroglobulin is one of the confirmed late onset genes leading to an increased risk for AD
ip t
(Blacker et al., 1998; Kovacs, 2000). Furthermore, elevated 2-macroglobulin levels in the
cr
blood of patients with AD validate the correlation between this A-interacting protein and AD pathogenesis (Hye et al., 2006; Zabel et al., 2012).
us
Similarly, 1-antichymotrypsin was reported to interact with A; however, its role in A aggregation is controversial. Certain studies suggest that 1-antichymotrypsin interacts with
an
A to stimulate A fibrillization in vitro and plaque deposition in a mouse model of AD (Ma
M
et al., 1994; Nilsson et al., 2001), while other studies reported that 1-antichymotrypsin inhibits A fibrillization and promotes disaggregation of A fibrils (Eriksson et al., 1995).
d
The exact functions and mechanisms of these interactions with A require further
Ac ce pt e
investigations; however, it is conceivable that interactions between A and plasma proteins affect the fate of A by modulating the aggregation process and clearance efficacy, which play critical roles in AD pathogenesis. Furthermore, AD-related alterations in the plasma levels of these interacting proteins could indicate disease progression and enable possible therapeutic interventions (Han et al., 2011a; Han et al., 2014; Velayudhan et al., 2012). Numerous blood proteins bind directly to A, and prevent the formation of A fibrils or accelerate A fibrillization. High density lipoproteins (HDL), including ApoA-I, ApoA-II, ApoE, clusterin, and serum amyloid A, are the main serum proteins that bind directly to A (Wilson et al., 2006). In the case of serum amyloid P (SAP), the literature is controversial. One study suggests that the component of SAP accelerates the formation of amyloid fibrils at unsaturated physiological concentrations of A42, and stabilizes the amyloid fibril (Mold et al., 2012), while another study proposes that SAP binds A peptides, inhibits fibril formation,
Page 13 of 68
and increases the solubility of Aβ (Janciauskiene et al., 1995).
3. Metal ions The relevance of metal ions in AD pathogenesis has been investigated in both the brain and
ip t
periphery in various studies. Metal ion homeostasis is perturbed drastically during AD
cr
pathogenesis, and diverse proteins crucial in AD pathology interact with transition metals. Notably, several metal ions affect A polymerization, nucleation, and plaque formation.
us
Recently, metal ions have been suggested to play a dual role in AD, which makes the
an
appreciation of metal ions complex and confusing in AD, with regard to both etiology and possible therapeutic strategies by utilizing metal chelators.
M
3.1 Copper
Copper (Cu) is one of the ions implicated in AD, and serum copper levels are higher in
d
patients with AD than in control subjects (Brewer et al., 2010) with a cutoff value of 16
Ac ce pt e
mol/L (Squitti et al., 2002). In the brain, Cu is concentrated in the extracellular compartment and in the amyloid plaques, which suggest the possibility of an interaction between Cu and A (Atwood et al., 1998; Lovell et al., 1998). However, it is controversial whether Cu/A interactions increase or inhibit A aggregation (Atwood et al., 1998; Faller, 2009; Raman et al., 2005). In addition to direct Cu/A interactions, even low levels of Cu modulate A production and clearance in the brain (Singh et al., 2013). In a mouse model of AD, Cu accumulates in the brain capillaries and parenchyma, and this accumulation is related to increased A production, neuroinflammation, and reduced A clearance through the downregulation of LRP1 (Singh et al., 2013). Furthermore, oxidative stress and neuronal toxicity, induced by hydrogen peroxide and toxic hydroxyl radicals, reduce Cu(II) to Cu(I) through Cu/A interactions (Hureau and Faller, 2009). Therefore, Cu affects A production, clearance, aggregation, and fibrillization through diverse mechanisms, either directly or
Page 14 of 68
indirectly. This is a strong evidence for the role of Cu in AD pathogenesis as an inorganic binding partner of A. Furthermore, several lines of evidence suggests that Cu binds not only to A, but also to tau, and thus exacerbates both amyloid and tau pathology in AD (Kitazawa et al., 2009; Ma et al., 2005; Martic et al., 2013).
ip t
3.2 Zinc
cr
Zinc (Zn) is distributed ubiquitously in the normal brain, and its level significantly increases in the brain (including the hippocampus and cortex) of patients with AD (Deibel et al., 1996;
us
Religa et al., 2006). Synaptic vesicular Zn levels are regulated by the transporter, ZnT3, which is essential for memory maintenance and normal cognitive function (Adlard et al.,
an
2010). Disturbed synaptic Zn levels in the ZnT3 knockout mice induce a significant decrease
M
in key synaptic proteins and synaptic density in the hippocampus, and cause age-dependent deficits in learning and memory, and thus might phenocopy AD. Ever since Zn levels were
d
found to be significantly higher in the serum and hippocampus of patients with AD than in
Ac ce pt e
controls (Danscher et al., 1997; Rulon et al., 2000), Zn has attracted much attention, as it was also reported to bind to A directly via a special binding site at the hydrophilic region of the N-terminus (Kozin et al., 2001). Similar to Cu or other A-interacting proteins, Zn is enriched in amyloid plaques and concentrated in the blood cells of patients with AD, and Zn/A interaction facilitates A aggregation (Mantyh et al., 1993; Suh et al., 2000). Interestingly, Zn is also involved in tau pathology by increasing tau hyperphosphorylation and aggregation (Sun et al., 2012; Xiong et al., 2013). Zn inactivates protein phosphatase (PP) 2A and induces tau hyperphosphorylation through the Src-dependent phosphorylation of PP2A at Y307 (Xiong et al., 2013). Zn was reported to elicit biphasic effects by initiating deleterious A deposition, redirecting A deposition towards amorphous aggregation, and quenching oxidative stress (Cuajungco and Faget, 2003; Huang et al., 2000; Rezaei-Ghaleh et al., 2011). Similarly, Cu/A
Page 15 of 68
complexes mediate cellular toxicity through oxidative mechanisms while they play a protective role by preventing the formation of amorphous aggregates from forming toxic fibril (Cuajungco and Faget, 2003; Suzuki et al., 2001; Yoshiike et al., 2001). Possibly, dual effects of metal ions on A-induced toxicity may occur in an A aggregation status dependent
ip t
manner, because A monomers sequestrate metal ion-induced oxygen radicals and protect
cr
neurons, whereas A aggregates induce the formation of oxygen radicals and neuronal death (Hou and Zagorski, 2006; Zou et al., 2002). Bifunctional compounds with binding motifs to
us
both metal (Cu, Zn) and A is used to inhibit the metal-mediated A42 aggregation and disaggregates amyloid fibrils (Sharma et al., 2012). Unexpectedly, increased formation of
an
neurotoxic soluble A42 due to inhibition of A aggregation and fibril disaggregation
be the simple answer in AD.
d
3.3 Iron
M
increases cellular toxicity, which apply therapeutic strategy to inhibit A aggregation may not
Ac ce pt e
In contrast to the extracellular localization of Cu and Zn, iron (Fe) is accumulated intracellularly during AD pathogenesis, leading to oxidative injury and neurodegeneration through redox-generated free radicals (Bush, 2013; Smith et al., 1997). Ferroxidase activity of the neuronal ferroxidase APP, which interacts with ferroportin to export Fe from the cells, is decreased in AD via the inhibition of Zn in the extracellular amyloid mass. Therefore, there is a pathological correlation between intracellular Fe accumulation and extracellular Zn deposition in the amyloid plaques (Bush, 2013; Duce et al., 2010; Smith et al., 1997). Fe binds to the first 16 amino acid residues of A at physiological pH (Bousejra-ElGarah et al., 2011), and redox-active Fe evokes A toxicity by causing cellular oxidative stress and lipid oxidation (Rottkamp et al., 2001). Furthermore, Fe binds to tau neurofibrillary tangles, and induces oxidative stress depending on the microenvironmental redox balance (Sayre et al., 2000). Tau maintains intracellular Fe levels by regulating APP trafficking and modulating the
Page 16 of 68
ferroxidase activity of APP; therefore, cognitive impairment and parkinsonism caused by brain atrophy and Fe accumulation in the tau KO mice are completely rescued by treatment with the Fe chelator clioquinol (Bush, 2013; Lei et al., 2012). 3.4 Aluminium
ip t
Aluminium (Al) is also a suspected risk factor for AD and the enhancement of A
cr
aggregation via its direct influence on aggregation and deposition processes (Kawahara et al., 1994; Neri and Hewitt, 1991). The presence of Al induced the conformational transition of
us
A40 from -helical to a -sheet and also AlATP enhanced the formation of thioflavin T reactive A fibrils with a -pleated sheet conformation (Exley and Korchazhkina, 2001;
an
Exley et al., 1993; House et al., 2004). Unlike Cu or Zn, Al and Fe directly influence the
M
precipitation of A -sheets, and the combination of these metals with the -sheets of A promotes oxidative neurotoxicity and neurodegeneration (Exley, 2006). Al-induced AD-
d
related neurotoxicity might be initiated by the modulation of anabolism and catabolism for
Ac ce pt e
APP and A and by increasing the formation of A and ubiquitin in neurons (Banks et al., 1996; Campbell et al., 2000; Exley, 2005; Korchazhkina et al., 2002). Al inhibits several proteases including the serine protease plasmin, which cleaves A, and therefore, it might inhibit the A degradation activity of plasmin (Clauberg and Joshi, 1993; Korchazhkina et al., 2002; Zatta et al., 1993).
3.5 Therapeutic strategy targeting metal ions Therapeutic candidates for AD targeting metal ions in the brain have been actively tested. The strategy of this AD therapy is to modulate the interaction between A and metal ions and to redistribute metal ions in the brain. Because Al or Fe initiates and stabilizes the assembly of the -pleated amyloid form, chelation of these metal ions would be beneficial to prevent the formation of A fibrils (House et al., 2004). Similarly, treatment with chelators that bind bioavailable Cu or Zn, such as clioquinol and PBT2, decreased A deposits and increased
Page 17 of 68
soluble A levels in a mouse model of AD (Cherny et al., 2001), and significantly improved cognitive function in a randomized, double-blinded, placebo-controlled Phase IIa clinical trial (Faux et al., 2010; Lannfelt et al., 2008). Clioquinol and PBT2 have multi-mechanistic actions, including competition for metal ions against Aβ, and activation of cellular protective
ip t
signaling pathways by increasing the intracellular levels of these metals, as these
cr
chelator/metal complexes are easily transported across membranes (Crouch and Barnham, 2012). However, complexity of metal ion dynamics during AD pathogenesis will be the main
us
challenge in clinical trials testing therapeutic candidates targeting Cu or Zn in AD (Bayer et
an
al., 2003; Kessler et al., 2008; Lannfelt et al., 2008) (Table 1). Furthermore, considering the effects of other metal ions relevant to AD pathogenesis, including Fe and Al, dynamics of
M
various metal ions can influence not only the aggregation and metabolism of A, but also tau
d
activity during AD pathogenesis in parallel, which requires further studies.
Ac ce pt e
4. A-binding membrane components (receptors) To elicit their physiological functions, diverse forms of A need to interact with membrane proteins to signal towards intracellular compartments or to be internalized during AD pathogenesis. Probing into these events is regarded as one of the most promising ways to prevent AD or delay its pathological progression. Therefore, it is critical to understand the cellular membrane proteins that bind A, and their expression levels and propensities to interact with A to initiate cellular downstream signaling (Fig. 2). 4.1 Receptor for advanced glycation end products Receptor for advanced glycation end products (RAGE) is a single transmembrane protein that binds to multiple ligands. Ever since RAGE was reported as the cellular membrane receptor of A, RAGE-mediated cellular signaling and its consequences have attracted much attention,
Page 18 of 68
as they are especially relevant to AD pathology (Han et al., 2011b; Yan et al., 1996; Yan et al., 2000). RAGE interacts with diverse forms of A including monomeric, oligomeric, and fibrillar forms (Sturchler et al., 2008; Verdier et al., 2004); however, the oligomeric form of A activates RAGE to a greater extent than the monomer form, and initiates inflammation
ip t
and tissue damaging processes (Herold et al., 2007). Kinetic studies demonstrated that
cr
RAGE/A interaction is fairly specific with Kd values ranging from 40 to 57 nM in different cell types (Yan et al., 1998). Additionally, RAGE/A interaction is dependent upon the
us
aggregation status of A and the binding sites in RAGE. The examination of RAGE binding sites using different forms of A and various inhibitors indicated that the Vd domain of
an
RAGE is responsible for A oligomer-induced apoptosis in SHSY-5Y cells and rat cortical
(Sturchler et al., 2008).
M
neurons, whereas the C1d domain of RAGE is involved in A aggregate-induced apoptosis
d
Depending on cell types or structures, such as cerebral vessels, microglia, and neurons,
Ac ce pt e
diverse ligands activate RAGE and thus various downstream signaling events including oxidative stress, activation of extracellular signal-related kinases (ERK), p38, and nuclear factor kappa B (NF-B) (Bianchi et al., 2007; de Arriba et al., 2003; Han et al., 2011b; Huttunen et al., 1999; Origlia et al., 2008; Poelmans et al., 2011; Riehl et al., 2009; Taguchi et al., 2000; Vazzana et al., 2009; Yan et al., 1996) (Fig. 2). The RAGE/A interaction induces cellular dysfunction and cytotoxicity through different signaling events, including oxidative stress and ERK activation, and is involved in mitochondrial dysfunction, neuronal toxicity, and synaptic dysfunction induced by increased A generation, intracellular transport, and RAGE expression (Arancio et al., 2004; Cho et al., 2009; Origlia et al., 2008; Takuma et al., 2009; Yan et al., 1996). Notably, elevated RAGE expression in neurons and microglia of animal models of AD and patients with AD implies that RAGE/A interaction may act as positive feedback mechanism during AD progression (Choi et al., 2014; Yan et al., 1998).
Page 19 of 68
Furthermore, RAGE overexpression increases the amount of A deposits and plaques clearly demonstrating the deleterious effect of this membrane receptor in the pathological progression of AD (Cho et al., 2009). Besides acting as a mediator of A-induced neuronal toxicity, RAGE serves as the primary
ip t
route for A to cross the BBB and enter the brain, which plays a critical role in AD
cr
pathogenesis (Deane et al., 2003; Deane and Zlokovic, 2007; Mackic et al., 1998; Yan et al., 1996). Peripheral A levels greatly impact A level and clearance in the central nervous
us
system; therefore, expression level and function of RAGE in the BBB is a crucial factor for
an
regulating cerebral Aβ levels (Marques et al., 2009; Sutcliffe et al., 2011). RAGE/A interactions result in the translocation of peripheral A into the brain across the BBB to
2003). Therefore, blockade of RAGE
M
increase cerebral A levels (Deane et al., 2003; Kawarabayashi et al., 2001; Matsuoka et al., in the BBB using a specific RAGE inhibitor (FPS-
d
ZM1) inhibits circulating A 40 and 42 to enter the brain, and therefore rescues from
Ac ce pt e
cognitive impairment caused by increased A40 and 42 levels in a mouse model of AD (Deane et al., 2012). Specifically, a region-specific inhibitor of RAGE may selectively antagonize a specific form of A and block a particular signaling cascade that is harmful to neurons. Additionally, interaction of A and RAGE in the BBB induced the expression of proinflammatory cytokines and endothelin-1, which might influence AD pathophysiology (Deane et al., 2003). Furthermore, another study reported that interaction of A and RAGE in cerebral endothelial cells disrupts the tight junctions in the BBB through the Ca2+-calcineurin signaling pathway, alters the integrity of microvessels close to the A plaques, and increases endothelial RAGE expression and matrix metalloprotease (MMP) secretion in a mouse model of AD (Kook et al., 2012). In addition, clinical trials for RAGE inhibitors are under investigation, including the phase III trial of TTP488 and the completed phase II trial for the oral inhibitor PF-04494700 (Burstein et al., 2014; Galasko et al., 2014; Sabbagh et al.,
Page 20 of 68
2011)(ClinicalTrials.gov identifier: NCT02080364, NCT00566397, Table 1). Therefore, RAGE regulates the cerebral A levels through diverse mechanisms. 4.2 Low-density lipoprotein receptor-related protein Low-density lipoprotein receptor-related protein (LRP) is a endocytic transmembrane
ip t
receptor with multi-ligand binding, belonged to low-density lipoprotein receptor (LDLR)
cr
family (Zerbinatti and Bu, 2005). LRP is expressed in the endothelial cells of the brain, and mediates rapid ligand endocytosis and signal transduction (Herz and Marschang, 2003; Herz
us
and Strickland, 2001; Shibata et al., 2000). Even though RAGE is the primary transporter of A across the BBB into the brain, accumulating evidence supports that LRP interacts with A
an
and is involved in the clearance of cerebral A by the endocytosis/transcytosis of A across
M
the BBB out of the brain (Deane et al., 2004; Donahue et al., 2006; Shibata et al., 2000). This LRP/A interaction and following LRP-dependent A was demonstrated in cellular context
d
of BBB, not in other cell types including fibroblasts or neuroblastoma cells expressing LRP1
Ac ce pt e
(Yamada et al., 2008). Accordingly, there is an increased expression of RAGE within the microvasculature of the hippocampus in AD compared to that in normal controls. By contrast, minimal LRP staining is observed in brains with AD, and this reduced expression correlates with regional A accumulation in such brains (Donahue et al., 2006; Shibata et al., 2000). In astrocyte, low-density lipoprotein receptor (LDLR) expressed mediate A uptake and degradation by direct interaction between LDLR and A, regardless of the presence of A (Basak et al., 2012). LDLR regulates brain A levels and the overexpression of LDLR could enhance A transport to lysosomes and promotes A degradation. LRP is also expressed in the neurons of the cortex and hippocampus (Bu et al., 1994; Tooyama et al., 1995; Wolf et al., 1992). LRP also mediates the neuronal A uptake and clearance in both a direct and indirect manner (Bu et al., 1994; Fuentealba et al., 2010; Tooyama et al., 1995). Receptor-mediated endocytosis is suggested as one of the neuronal
Page 21 of 68
mechanisms for A clearance by LRP1 (Kanekiyo et al., 2013). Conditional knockout of LRP1 exacerbate brain A levels and plaque deposition in cortex of APP/PS1 mice. Neuronal deletion of LRP1 in mice forebrain causes the breakdown of brain lipid homeostasis leading to dendritic spine loss, synaptic degeneration, memory loss, and finally neurodegeneration
ip t
(Liu et al., 2010). However, there are conflicting results on in vivo LRP study using LRP-
cr
overexpressing transgenic mice. Overexpression of LRP1 in the brain of PDAPP mice results in the increased soluble brain A (monomers/dimers), but not A plaque, which is
us
significantly related to spatial learning and memory deficit (Zerbinatti et al., 2004). Also followed study demonstrates that LRP1 overexpression in PDAPP mice increases membrane-
an
associated A 42 and intraneuronal A42 in the region of hippocampus or frontal cortex
M
(Zerbinatti et al., 2006). In addition, LRP influences the prion protein mediated toxicity of A oligomers by modulating cell surface interactions, the internalization process, and spreading
Ac ce pt e
4.3 Prion protein
d
of intracellular toxicity mediated by A oligomers (Rushworth et al., 2013).
Prion protein (PrP) has been recently identified as a critical high affinity receptor for toxic A assemblies that mediates diverse downstream toxic events including impairments in synaptic plasticity, memory, and neuronal survival (Alier et al., 2011; Bate and Williams, 2011; Gimbel et al., 2010; Kudo et al., 2012; Lauren et al., 2009). Inhibition of long term potentiation (LTP) by A occurs in a PrP-dependent manner (Freir et al., 2011), and is mediated by A protofibrils with a triple helical nanotube structure, rather than by the monomer or oligomer forms, while A fibrils inhibit LTP in a PrP-independent manner (Nicoll et al., 2013). Considering downstream signaling, soluble A assemblies interact with cellular PrP, and this event activates Fyn, which phosphorylates the NR2B subunit of Nmethyl-D-aspartate (NMDA) receptors, and relocalizes NMDA receptors, leading to neuronal impairments (Um et al., 2012) (Fig. 2). The process also results in dendritic spine loss and
Page 22 of 68
lactate dehydrogenase release after an initial increase of NMDA receptors, followed by the loss of these receptors. Therefore, anti-cellular PrP monoclonal antibodies are suggested as a new potential therapy for AD, because these antibodies improve behavioral effects of AD in a
prevent LTP inhibition and PrP/A interaction (Freir et al., 2011).
cr
4.4 Ephrin type-B receptor2
ip t
mouse model (Chung et al., 2010), and specific antibodies against helix-1 of PrP effectively
The receptor tyrosine kinase Ephrin type-B receptor2 (EphB2) is closely related with synaptic
us
function, including LTP, by modulating the NMDA-dependent Ca2+ influx and downstream transcription factors (Benilova and De Strooper, 2013; Henderson et al., 2001; Takasu et al.,
an
2002) (Fig. 2). The reduction of hippocampal EphB2 level was detected in transgenic mice
M
expressing the human APP and in the postmortem tissue from AD patients compared with non-transgenic controls and non-demented controls, respectively, suggesting the clinical
d
relevance of EphB2 in AD pathogenesis (Cisse et al., 2011; Simon et al., 2009). A
Ac ce pt e
oligomers bind directly to EphB2, and increase the proteasomal degradation of EphB2, which is another key factor of the A-mediated inhibition of LTP and subsequent memory impairment (Cisse et al., 2011; Simon et al., 2009). Increased levels of EphB2 in the dentate gyrus of mice that model AD reversed not only the impairment of NMDA receptor mediated LTP, but also memory decline (Cisse et al., 2011). 4.5 75-kD neurotrophin receptor
The 75-kD neurotrophin receptor (p75NTR), which leads to neuronal death in AD, is another receptor for specific A interactions (Yaar et al., 1997). A activates p75NTR, but not Trk, and mediates the downstream activation of the intracellular death domain of p75NTR and JNK phosphorylation, which induces apoptosis in hippocampal neurons (Diarra et al., 2009; Dinamarca et al., 2012). Similarly, p75NTR enhances A generation via the -cleavage of APP, while tyrosine kinase receptor A (TrkA), another neurotrophin receptor, reduces APP
Page 23 of 68
cleavage. A generation is increased in the brain during normal aging, which results from the upregulation of p75NTR signaling by switching from the TrkA-mediated signaling to the p75NTR-mediated signaling (Yaar et al., 1997). 4.6 Serpin-enzyme complex
ip t
The serpin-enzyme complex (SEC) receptor is a transmembrane protein expressed on diverse
cr
cell types, and is identified as a receptor for 1-antitrypsin/elastase complexes (Joslin et al., 1992). Soluble A interacts specifically with the SEC receptors in hepatoma and neuronal
us
cells, and SEC receptors mediate the internalization and metabolism of A (Boland et al., 1995). Amino acid residues 31-35 of the A peptide are identified as the critical region for the
an
association of SEC receptor and A. Inability of the SEC receptor to bind the aggregated
M
form of A, such as A fibrils, implies that this receptor exerts beneficial effects, including
al., 1996; Verdier et al., 2004).
Ac ce pt e
4.7 Insulin receptor
d
A clearance, rather than mediating the cytotoxic effects induced by fibrillar A (Boland et
It is not surprising that A binds directly to the insulin receptor, because insulin and A shares many common features including their consensus sequence, which serves as the substrate for insulin-degrading enzymes (Kurochkin, 1998; Xie et al., 2002). A competes with insulin for binding to the insulin receptor (A: 16-26 amino acid residues, insulin: 21-30 amino acid residues), and inhibits the action of insulin, which is tightly linked to insulin resistance caused by the excessive amount of A during AD pathogenesis. In addition, A blocks insulin receptor signaling directly by inhibiting the autophosphorylation of the insulin receptor (Ling et al., 2002). 4.8 Neurotransmitter receptors Numerous neurotransmitter receptors bind A, and these associations play a critical role in neuronal function and the neurodegenerative pathophysiology of AD. The 7 nicotinic
Page 24 of 68
acetylcholine receptor (7nAChR) is a neuronal pentameric cation-selective channel complex modulating the permeability of Ca2+ and Na+ (Breese et al., 1997; Verdier et al., 2004). It is an integral membrane protein, which is highly expressed in basal cholinergic neurons projecting to the hippocampus and cortex (Breese et al., 1997). A and 7nAChR can be co-
ip t
immunoprecipitated, and both are found in neuritic plaques in the brains of patients with AD
cr
(Wang et al., 2000a). The consequence of the 7nAChR/A interaction is still controversial; both agonist- and antagonist-like effects are suggested (Dougherty et al., 2003; Liu et al.,
us
2001). Agonist-like effects are observed in the presynaptic nAChRs inducing a sustained increase in Ca2+ levels at the presynaptic terminals (Dougherty et al., 2003; Mehta et al.,
an
2009), while other studies demonstrated that A inhibits neuronal 7nAChRs in rat
M
hippocampal slices and cultures (Liu et al., 2001; Pettit et al., 2001), and prevents the Ca2+ influx in synaptosomes (Lee and Wang, 2003; Wang et al., 2009a). It has been shown recently
d
that the agonistic effect of A on the 7nAChRs in presynaptic nerve terminals is mediated
Ac ce pt e
by receptor-associated lipid rafts (Khan et al., 2010). Similarly, tau phosphorylation is stimulated by the interaction of A and 7nAChRs (Wang et al., 2003). The binding affinity between A42 and 7nAChR is exceptionally high, within the picomolar concentration range, which suggests that this interaction might serve as a precipitating factor in amyloid plaque formation contributing to the degeneration of cholinergic neurons (Wang et al., 2000b). A binds and blocks 7nAChR reversibly through the extracellular N-terminal domain of the receptor, which is a non-competitive and voltage/use-independent process (Liu et al., 2001). Recent clinical study of the novel 7nAChR agonist, ABT-126, has suggested a promising result (Gault et al., 2015) and this kind of 7nAChR agonist may show their effectiveness through dual mechanism of receptor stimulation and blocking of A binding (Table 1). The NMDA receptor is another neurotransmitter receptor that interacts with A, and this binding influences synaptic function (Danysz and Parsons, 2012). Co-immunoprecipitation
Page 25 of 68
studies revealed that the interaction between NR1 or NR2A and soluble A oligomers in present in excitatory pyramidal neurons, but not in GABAergic neurons, and the interaction induces synaptic loss (Lacor et al., 2007; Venkitaramani et al., 2007). Binding of A to the NMDA receptor influences the internalization and pathogenic effect of A, which is blocked
ip t
by NMDA receptor antagonists (Bi et al., 2002). Selective NMDA receptor antagonists
cr
inhibit not only the internalization of A, but also the upregulation of cathepsin D and microglial activation. Similarly, oxidative stress induced by A application in vivo is
us
ameliorated by NMDA receptor antagonists (Parks et al., 2001). A activates NF-B through the NMDA receptor and via activation of the NMDA-Src-Ras-like protein, mitogen-activated
an
protein kinase (MAPK), and phosphatidylinositol 3-kinase (PI3-k) signaling pathway in
M
cultured cerebellar cells, which is regarded neuroprotective in response to A (Kawamoto et
related to the integrins.
Ac ce pt e
4.9 Integrin
d
al., 2008). Furthermore, in terms of A internalization, function of NMDA receptors is tightly
Integrins are heterodimers compiled of and glycoprotein transmembrane subunits, and they are related to the uptake of microorganisms such as bacteria and virus. Integrins bind directly to A, and cooperate with NMDA receptors to regulate A internalization (Bi et al., 2002; Isberg and Tran Van Nhieu, 1994). As mentioned above, NMDA receptor antagonists completely block A internalization, cathepsin D upregulation, and microglia activation, while antagonists of integrins enhance these phenomena; thus, suggesting that these two receptors work cooperatively during A internalization. In particular, fibronectin receptor 51 is highly expressed in the hippocampus, and mediates the internalization of non-fibrillar A by binding to the Arg-Gly-Asp (RGD)-like sequence of A, and thus enhances A clearance (Ghiso et al., 1992; Matter et al., 1998; Sabo et al., 1995). Therefore, 51 has a protective effect against A deposition/fibrillization, A-mediated toxicity, and apoptosis.
Page 26 of 68
4.10 Leukocyte immunoglobulin-like receptor B2 Besides PrP and EphB2, leukocyte immunoglobulin-like receptor B2 (LilrB2; paired immunoglobulin-like receptor B, PirB, in mice) has recently been found to bind A oligomers directly, and is involved in memory loss and the impairment of synaptic plasticity in a
ip t
transgenic model of AD (Kim et al., 2013). PirB (LilrB2) is a typical receptor of the
cr
immunoglobulin-like receptor family, and was originally thought to be expressed in a wide range of immunogenic cell types including B cells, mast cells, dendritic cells, and
us
macrophages (Takai, 2005). In the immune system, PirB inhibits receptor-mediated activation signals by interacting with other activating receptors. In addition, it contributes to major
an
histocompatibility complex (MHC) recognition (Takai, 2005). Recently, PirB has been found
M
in neurons and synapses (Atwal et al., 2008; Syken et al., 2006). Similar to EphB2, PirB inhibits LTP, alters synaptic plasticity, and induces behavioral impairments in a mouse model
d
of AD through the direct binding of PirB and A oligomers; these alterations can be rescued
Ac ce pt e
by PirB deletion (Kim et al., 2013). The downstream mechanism for the PirB/A oligomer interaction involves cofilin recruitment and activation by phosphorylation in an Adependent manner, as demonstrated in vitro and in vivo. Furthermore, alterations in cofilin phosphorylation are detected in patients with AD, which implies an AD-related role for PirB/A oligomer interaction. 4.11 Membrane lipids
A interacts not only with membrane-bound receptors, but also with the cell membrane directly. A interacts with the plasma membrane and membrane of subcellular organelles including the Golgi complex, lysosomes, and endoplasmic reticulum (Terzi et al., 1997; Waschuk et al., 2001). These interactions influence the properties (fluidity and structure) and function of the membrane through releasing lipid molecules from the neuronal plasma membrane, A fibrillogenesis, and abnormal Ca2+ entry into the cell through amyloid
Page 27 of 68
channels (Talaga and Quere, 2002). A has limited solubility in aqueous solutions, its structure is transformed into sheets at an acidic pH, and it binds electrostatically to the outer region of the polar head group of the membrane, but does not penetrate the polar groups (Terzi et al., 1997). Similarly, A binding studies using surface plasmon resonance revealed
ip t
that a large proportion of A is bound to membrane lipids, and this interaction disrupts the
cr
lipid structure and fluidity of the membrane, which might influence the localization and function of various receptors and channels on the cell membrane (Small et al., 2007). Lipid
us
compositions of different membranes influence A aggregation (Waschuk et al., 2001). A fibrillogenesis is accelerated in the presence of plasma lipid vesicles as fiber bundles along
an
the bilayer, driven by the interaction of A with the lipid surface. However, interaction of A
M
with the Golgi membrane does not enhance A fibril formation; it increases membrane fluidity through possible stabilization of A by the interaction between A and lipid head
d
groups in the Golgi and induction of interfacial packing defects. Furthermore, the lipid
Ac ce pt e
composition of the membrane, including the presence of gangliosides and cholesterol, plays a critical role in amyloid formation, because GM-1 ganglioside accelerates A fibril formation by binding Aβ possibly serving as seed (Kakio et al., 2002). In the other hand, soluble form of Aβ oligomers are sequestered and bound to GM1 ganglioside on brain membranes, more rapidly compared to monomer (Hong et al., 2014). This interaction between Aβ oligomer and GM-1 ganglioside has a critical role in Aβ–mediated synaptic dysfunction because the interference of this interaction prevented the impairment of long-term potentiation in mouse hippocampus slices. Similarly, diverse factors regulate the association between A and membrane lipid, including ions of Cu2+, Zn2+, pH, and cholesterol (Curtain et al., 2003). 4.12 Amyloid precursor protein Interestingly, A interacts with its own precursor protein, APP (Lorenzo et al., 2000). APP is a type I transmembrane protein with a large extracellular domain of N-terminus and a short
Page 28 of 68
C-terminal cytoplasmic tail. APP plays diverse developmental and functional roles including synaptic activity, response to stress, and injury repair (Panegyres, 2001). In addition, APP may function as a cell surface receptor and mediate cell adhesion and neurite outgrowth (Breen et al., 1991; Kang et al., 1987; Milward et al., 1992). In cortical neurons, its binding
ip t
affinity to the toxic fibrillar A is drastically increased compared with that to the soluble A,
cr
showing a binding affinity to fibrillary A at the nanomolar concentration range (Lorenzo et al., 2000). Furthermore, neuronal toxicity of A is mediated by the APP/A interaction,
us
because APP-null neurons exhibit reduced neurotoxicity to A. This study also showed that fibrillar A binds mainly to the cell membrane associated form of APP, but a much lower
an
interaction is detected with secreted soluble APP, which implies that a certain part of the C-
M
terminal residue or the transmembrane orientation are prerequisite for APP/A interaction.
d
5. Intracellular A-interacting proteins
Ac ce pt e
In addition to the extracellular accumulation, intracellular accumulation of A is an early event in AD pathogenesis, and the region of intraneuronal A detection is more prone to the brain region of AD pathology (hippocampus and the entorhinal cortex) in mild cognitive disorder (Gouras et al., 2000; LaFerla et al., 2007). Therefore, binding partners of intracellular A would be direct targets or mediators of intracellular A toxicity. 5.1 Endoplasmic reticulum-associated A peptide binding protein Endoplasmic reticulum-associated A peptide binding protein (ERAB) binds to A and mediates A neurotoxicity, because blocking ERAB prevents A-mediated toxicity, and its overexpression enhances toxicity (Yan et al., 1997). ERAB is an intracellular polypeptide without a signal peptide or transmembrane-spanning domain, and is considered as a hydroxysteroid dehydrogenase enzyme. Co-immunoprecipitation of ERAB and A, and overexpression of neuronal ERAB in A-treated cells suggest that intracellular binding of
Page 29 of 68
ERAB with A plays a critical role in neuronal dysfunction in AD. Additionally, extracellular A exposure upregulates ERAB, and redistributes intracellular ERAB to the plasma membrane. ERAB is an intracellular target of A, and consequently induces cellular stress and apoptosis during AD pathogenesis.
ip t
5.2 Chaperone proteins
cr
Chaperone proteins have been suggested to bind to A and modulate the metabolism, function, and toxicity of intracellular A. Using transgenic Caenorhabditis elegans, six
us
chaperone proteins were identified to bind to intracellular A, including two in the heat shock protein (Hsp) 70 family and three Hsp16 proteins (B-crystallin-related small heat shock
an
proteins), suggesting their direct and early functional contribution to age-associated
M
neurodegenerative diseases (Fonte et al., 2002). Furthermore, numerous small heat shock proteins, including Hsp20, Hsp27, HspB2, show extracellular expression, and colocalize with
d
A in amyloid plaques (Wilhelmus et al., 2006).
Ac ce pt e
5.3 X11-like, B-crystallin and lysozyme
Indirectly, intracellular protein binds to APP, and modulate the amyloidogenic process and metabolism of APP, which has a critical effect on AD pathogenesis. X11-like (X11L) is a neuronal adapter protein with a phosphotyrosin-binding (PTB) domain and two C-terminal PDZ domains, and suppresses the amyloidogenic process of mature APP by accumulating immature APP in the early secretory pathway (Saito et al., 2011). B-crystallin, the small heat-shock protein family, shows increased expression in brains from AD patients and immunoreactivity to B-crystallin in astrocyte and microglia is detected mainly in the area with senile plaques and neurofibrillary tangles (Renkawek et al., 1994). The core domain of B-crystallin binds to A, and prevents the A aggregation process, even though its structure is not altered upon A binding (Das et al., 2014). Lysozyme also binds to A and inhibits the A aggregation, competing with B-crystallin for inter-peptide interaction
Page 30 of 68
with different A binding dynamics.
6. Mitochondrial A-binding components Mitochondrial dysfunction is an early event observed during AD pathogenesis, and A-
ip t
mediated mitochondrial dysfunction has been well investigated (Canevari et al., 2004;
cr
Tillement et al., 2011). Diverse AD-related phenomena are observed in the mitochondria, including alterations in membrane permeability, dysfunction of respiratory enzymes, altered
us
mitochondrial fission/fusion balance, subsequent mitochondrial fragmentation, and abnormal localization (Casley et al., 2002; Cha et al., 2012; Moreira et al., 2002; Santos et al., 2010;
an
Wang et al., 2009b). Therefore, mitochondria are regarded as one of the main targets of A-
M
mediated toxicity, and much effort has been devoted to elucidate the relevant mitochondrial proteins and their mechanisms involved in A-induced mitochondrial toxicity (Fig. 3).
d
6.1 Cytochrome c oxidase
Ac ce pt e
Cytochrome c oxidase is a component of a respiratory chain enzyme complex localized in the mitochondrial inner membrane. This system utilizes electrons from NADH to maintain the membrane potential that is necessary for ATP generation. After passing electrons through this redox system, they are finally transferred to oxygen by cytochrome c oxidase in complex IV (Mick et al., 2011). Cytochrome c oxidase has 13 subunits, and, importantly, the aminoterminal region of cytochrome c oxidase subunit 1 binds to A 1-42, and aggregates Aβ in the brains with AD (Hernandez-Zimbron et al., 2012). This interaction results in a stable helixhelix structure, and induces deleterious effects during AD pathogenesis, including the impaired activity of respiratory chain complex IV and neuronal metabolic dysfunction (Hernandez-Zimbron et al., 2012). The direct binding of cytochrome c oxidase and A might explain the AD-related reduction in cytochrome c oxidase activity and the decrease of both oxidative stress and plaque formation in a transgenic animal model of AD with cytochrome c
Page 31 of 68
oxidase deficiency (Fukui et al., 2007; Pickrell et al., 2009). 6.2 A-binding alcohol dehydrogenase A-binding alcohol dehydrogenase (ABAD) is an enzyme composed of 261 amino acid residues localized in the mitochondrial matrix of neurons, and it directly interacts with
ip t
mitochondrial A in the mitochondria of a transgenic mouse model of AD and in patients
cr
with AD (Chen and Yan, 2007; Lustbader et al., 2004). Interaction of ABAD and A promotes neuronal oxidative stress, mitochondrial dysfunction, and cell death, leading to
us
hippocampal dysfunction and memory impairment (Lustbader et al., 2004; Pinho et al., 2014; Takuma et al., 2005). Prevention of the ABAD/A interaction ameliorates A accumulation
an
in the brain, and rescues from A-mediated apoptosis, free radical production, and
M
mitochondrial dysfunction in a mouse model of AD (Lustbader et al., 2004; Yao et al., 2011). Behavioral stress significantly aggravates AD-related pathologies, including oxidative stress,
d
mitochondrial dysfunction, and plaque formation, which are mediated by increased
Ac ce pt e
mitochondrial ABAD expression in the brain (Seo et al., 2011). This demonstrates that the expression level of ABAD is a critical factor for modulating A-mediated mitochondrial toxicity during AD pathogenesis.
6.3 Mitochondrial permeability transition pore Mitochondrial permeability transition pore (mPTP) is composed of several core proteins, including voltage-dependent anion channel (VDAC), mitochondrial benzodiazepine receptor, adenine nucleotide translocase (ANT), and cyclophilin D, which are localized in the outer and inner mitochondrial membranes (Halestrap et al., 2002). It plays a critical role in apoptotic and necrotic cell death, and has attracted much attention in AD, because A interacts with more than one component of the mPTP, and modulates pore opening. Cyclophilin D is a key factor that triggers the opening of mPTP by its translocation from the mitochondrial matrix to the mitochondrial inner membrane under oxidative and cellular stress
Page 32 of 68
(Andreeva et al., 1999; Connern and Halestrap, 1994; Henry-Mowatt et al., 2004). In studies, which performed genetic inactivation or deletion of cyclophilin D, mitochondrial permeability transition was regulated by cyclophilin D via modulating the sensitivity of mPTP to calcium overload and oxidative stress. Therefore, cyclophilin D deficits protect from
ip t
stress-induced cell death (Basso et al., 2005; Schinzel et al., 2005). During AD pathogenesis,
cr
cyclophilin D is a mitochondrial target of A mediated by their direct interaction resulting in subsequent mitochondrial dysfunction and leading to behavioral impairments, synaptic
us
dysfunction, and neuronal death. Notably, these effects can be rescued by cyclophilin D deficiency (Du et al., 2008; Du et al., 2011).
an
VDAC is another interacting partner of A in the mitochondria, localized in the
M
mitochondrial outer membrane, and it mediates the transport of metabolites in and out of the mitochondria (Colombini, 2012; Hodge and Colombini, 1997). Three VDAC isoforms have
d
been described (VDAC1, 2, and 3), and VDAC1 is the most widely expressed isoform in the
Ac ce pt e
brain (Yamamoto et al., 2006). VDAC1 expression is upregulated in the cortical tissue of patients with AD and in the cerebral cortex of APP overexpressing transgenic mice. Notably, VDAC1 interacts with A and this interaction is detected both in patients with AD and various transgenic mouse models of AD (Manczak and Reddy, 2012b). Interestingly, VDAC1 interacts not only with A, but also with phosphorylated tau, which is the second major pathological hallmark of AD. The interaction of VDAC with either A or phosphorylated tau results in abnormal operation of the mitochondrial pore, and leads to impairments in oxidative phosphorylation and mitochondrial function, possibly causing neuronal death (Manczak and Reddy, 2012b). Also, recent study has shown that A interacted with VDAC1, specifically in the N-terminal region, and induced mitochondrial dysfunction and mitochondria-mediated apoptosis, which was prevented by non-cell-penetrating VDAC1 Nterminal peptide or silencing VDAC1 expression (Smilansky et al., 2015).
Page 33 of 68
6.4 Mitochondrial enzymes Mitochondrial structural abnormalities are thought to be closely related to mitochondrial functional impairments during AD progression. Furthermore, the main cause of abnormal mitochondrial structure and morphology is the imbalance between fission and fusion (Wang
ip t
et al., 2009b; Wang et al., 2008). Diverse mitochondrial enzymes can be influenced by the
cr
direct interactions with A, which alter enzyme activities, followed by changes in mitochondrial structure and function, and finally result in mitochondrial impairment.
us
Dynamin-related protein Drp1 is one of the main GTPase proteins that maintain mitochondrial morphology and structure by regulating mitochondrial fission, together with
an
fission 1(Fis1) protein (Suen et al., 2008). Interestingly, Drp1 interacts with A in the frontal
M
cortex of patients with AD and in the cerebral cortex of transgenic mouse models of AD (Manczak et al., 2011). Drp1 expression is upregulated in AD, and this increase primarily
d
occurs in the early phase of AD. Furthermore, interaction between Drp1 and A increases
Ac ce pt e
with disease progression. This finding implies that abnormal mitochondrial dynamics are early events during AD pathogenesis (Manczak et al., 2011). In a subsequent study, it was shown that Drp1 also binds to hyperphosphorylated tau in neurons with AD, leading to increased GTPase activity, abnormal mitochondrial fragmentation, mitochondrial and synaptic dysfunction, neuronal damage, and ultimately cognitive impairment in AD (Manczak and Reddy, 2012a). Additionally, subunit of the F1F0-ATP synthase was suggested as an A-interacting mitochondrial protein (Schmidt et al., 2008). F1F0-ATP synthase, also known as complex V, is responsible for ATP production, ATP hydrolysis, and maintenance of the mitochondrial proton gradient. F1F0-ATP synthase also interacts with A at the surface of neuronal cells (Schmidt et al., 2008; von Ballmoos et al., 2009). The binding sequence of A to ATP synthase is fairly similar to that of a naturally occurring inhibitor of the ATP synthase complex in the mitochondria—inhibitor of F1, and the activity of ATP
Page 34 of 68
synthase is decreased through its interaction with A (Schmidt et al., 2008). The detailed mechanism of decreased ATP synthase activity in AD has been discovered that the direct interaction between ATP synthase subunit and A inhibited the glycosylation with O-linked -N-acetylglucosamine at Thr432 in ATP synthase, which resulted in impairments of both
ip t
ATPase activity and ATP production (Cha et al., 2015).
cr
The mitochondrial peptidasome, known as the presequence protease (PreP), is a metallopeptidase localized to the mitochondrial matrix (Alikhani et al., 2011; Falkevall et al.,
us
2006). The human PreP homologue degrades diverse forms of A, such as A1–40 and A1– 42, by direct interaction (Alikhani et al., 2011; Falkevall et al., 2006). Mitochondrial PreP
an
activity is lower in the temporal lobe of patients with AD than in controls; however, no
M
difference was observed in the cerebellum, which is spared from the accumulation and influence of A (Alikhani et al., 2011). A accumulation and increased mitochondrial
d
oxidative stress may correlate with a decreased PreP activity in AD.
Ac ce pt e
Mitochondria are one of the most vulnerable organelles affected by A. They act as repositories for diverse molecular targets for direct A interactions that might initiate and propagate AD. Therefore, it is a promising strategy for AD therapeutics to rescue mitochondrial function by modulating the expression or function of A-interacting mitochondrial proteins or by rescuing AD-related enzymatic imbalances and dysfunctions in the mitochondria.
7. A-interacting mediators of immune activation The innate immune response in AD pathogenesis is currently considered as one of the most critical issues in the field of AD research. Many studies have aimed to determine how immune cells are triggered by A itself or A-related signaling pathways, and how immune activation, including inflammatory responses, affects AD progression (Fig. 2).
Page 35 of 68
7.1 Toll-like receptors In terms of the A-induced microglial activation and inflammatory response, toll-like receptors (TLRs) may be one of the most essential mediators of A. TLRs are pattern recognition receptors expressed abundantly on innate immune cells with a prominent immune
ip t
reaction against pathogens (Akira, 2001; Gordon, 2002; Medzhitov, 2001). TLRs function as
cr
dimers, and often cooperate with co-receptors, such as cluster of differentiation (CD)14, to recognize pathogens (Baumann et al., 2010). TLR signaling is involved in A uptake and
us
clearance in the brain (Richard et al., 2008; Tahara et al., 2006). Notably, TLR2 is the primary A-binding receptor that initiates neuroinflammation (Liu et al., 2012). TLR2
an
activation induces inflammatory responses through diverse signaling pathways including
M
mitogen-activated protein 3 kinases (MAP3K), ERK, c-Jun N-terminal kinases (JNK), and p38 (Canton et al., 2013; Kariko et al., 2004; Strober et al., 2006) (Fig. 2). Furthermore,
d
TLR2 interacts with the fibrillar form of A and stimulates activation of microglia, which are
Ac ce pt e
critical components of AD pathogenesis (Jana et al., 2008). TLR2/fibrillar A42 engagement activates microglia, and consequently induces NO synthase, proinflammatory cytokines, and integrin markers, which are blocked in knockout animals or by the functional inhibition of TLR2 (Jana et al., 2008). Evidence suggests that both TLR2 and TLR4 are involved in the inflammatory response initiated by aggregated A, and specific antagonism of TLR2 and TLR4 causes ~50% and ~35% decrease in the A-induced response, respectively (Udan et al., 2008). Furthermore, fibrillar A fails to induce phagocytic responses and ROS production, or activate microglia without TLR2 or TLR4 function, as shown by the use of blocking antibodies in microglial cell lines or primary cultures from knockout mice (Reed-Geaghan et al., 2009). Accordingly, increased TLR2 and TLR4 expression was detected in the brains of APP-overexpressing transgenic mice and patients with AD, especially in a pattern associated with A plaque deposition in the entorhinal cortex (Letiembre et al., 2009; Walter et al.,
Page 36 of 68
2007). Additionally, TLR expression is closely associated with A-induced cellular toxicity, as A42 infusion greatly increases TLR2 expression in the hippocampus of wild type CD1 mice (Letiembre et al., 2009; Richard et al., 2008). Moreover, TLR2- and CD14-positive microglia are associated with A plaques in the cortex of APP overexpressing transgenic mice
ip t
(Letiembre et al., 2009; Richard et al., 2008). Similar to the central nervous system, clinical
cr
data shows increased TLR2 and TLR4 expression in peripheral blood mononuclear cells from patients with AD compared with that from controls (Zhang et al., 2012). Importantly,
us
microglial activation by TLR2 or TLR4 ligands increases the clearance of A in vitro and in vivo (Herber et al., 2007; Tahara et al., 2006), and a lipopolysaccharide (LPS)-derived
an
detoxified TLR4 agonist improves pathology in a mouse model of AD (Michaud et al., 2013).
M
Several mechanisms might explain this phenomenon, including the increased phagocytic activity of microglia by TLR activation or the TLR2-mediated upregulation of mouse G-
d
protein coupled formyl peptide receptor (mFPR2)-mediated A uptake (Chen et al., 2006).
Ac ce pt e
Therefore, ligands of TLR2 or 4 have been considered as new therapeutic candidates; however, it remains controversial whether TLR/A interaction, followed by microglial activation and induction of reactive oxygen species, is beneficial to AD pathology, because microglial activation is a complicated process, and can produce biphasic effects and diverse phenotypes depending on the environment (Mizuno, 2012; Morgan et al., 2005; Tahara et al., 2006; Walker and Lue, 2005).
7.2 Receptor for advanced glycation end products As discussed earlier, RAGE plays critical roles in A-mediated toxicity in neurons. This receptor is associated with the A-mediated activation of the immune response, and is localized at the surface of innate immunogenic cells (Fang et al., 2010; Yan et al., 1996). In addition, microglial RAGE/A interactions amplify inflammatory responses through microglial proliferation and migration (Fang et al., 2010; Yan et al., 1996). Microglial RAGE
Page 37 of 68
mediates A-induced synaptic dysfunction, including transient depression of basal synaptic functions and impairment of long term depression, which can be rescued by inhibiting microglial RAGE, but not by the suppression of RAGE in neurons (Origlia et al., 2010). Increased RAGE immunoreactivity was detected in the microglia of patients with AD,
ip t
primarily in the hippocampus (Lue et al., 2001). Additionally, RAGE/A engagement
cr
increases the expression and secretion of macrophage-colony stimulating factor (M-CSF) in both microglial cell cultures and brain-derived microglia from patients with AD, with a
us
significantly greater effect in microglia derived from the brains with AD than in those from the control brains (Lue et al., 2001). Furthermore, increased levels of M-CSF and A
an
upregulate RAGE expression, forming a positive feedback loop of microglial activation
M
induced by the RAGE/A interaction and increased M-CSF expression followed by RAGE expression, which might be a critical process during AD pathophysiology. Diverse
d
downstream signaling pathways are activated by microglial RAGE activation, which are
Ac ce pt e
shown in Figure 2 (Bianchi et al., 2007; Riehl et al., 2009). 7.3 CD36
CD36, a scavenger receptor, is expressed on monocytic lineage cells, such as microglia and macrophages. It binds to ligands with a diverse range of structures, and plays a critical role in the activation of innate immune responses. This scavenger receptor is an important mediator in the pathogenesis of AD, because lack of it abolishes A-mediated oxidative stress and cerebrovascular dysfunction in APP overexpressing mice (Park et al., 2011). Furthermore, CD36 is associated with cerebral amyloid angiopathy (CAA); it increases vascular amyloid deposition, resulting in subsequent cerebrovascular damage and dysfunction leading to cognitive impairment (Park et al., 2013). Evidence shows that A fibrils activate microglia and induce the secretion of proinflammatory cytokines by interacting with a receptor complex consisting of CD36, integrin-associated protein/CD47, and 61-integrin (Bamberger et al.,
Page 38 of 68
2003). This interaction is mediated by a tyrosine kinase-based downstream signaling cascade, and both antagonists and A peptide competitors of the CD36 receptor complex abolish the A-mediated stimulation of tyrosine kinase-based signaling and interleukin 1 production (Bamberger et al., 2003; Canton et al., 2013) (Fig. 2). The activation of tyrosine kinases Lyn
ip t
and Syk induce transient calcium release, which results in protein kinase C (PKC) and protein
cr
tyrosine kinase PYK2 (calcium sensitive tyrosine kinase) and then ERK1/ERK2 activation, leading to the generation of neurotoxic products including superoxide radicals (Combs et al.,
us
1999; McDonald et al., 1997). Furthermore, engagement of fibrillar A and this receptor complex induces a phagocytic response, which is mainly driven by 1 integrin, and is distinct
an
from the typical type I and type II phagocytic mechanisms (Koenigsknecht and Landreth,
7.4 Microglial receptors
M
2004).
d
Microglial class A scavenger receptor (SR) interacts with A fibrils via its collagen-like
Ac ce pt e
domain, and plays a critical role in microglial adhesion to fibrillary A (El Khoury et al., 1996). Furthermore, SR mediates the removal and clearance of A by its binding and uptake (Paresce et al., 1996). Additionally, A is a chemotactic agonist for immune response by binding to the FPR-Like-1 (FPRL1) receptor expressed on mononuclear phagocytes (microglial cells, monocytes, and monocytic cell lines) and inflammatory cells infiltrating the cerebral amyloid plaques in patients with AD (Le et al., 2001). FPRL1 is a seventransmembrane G protein-coupled receptor, and the association of FPRL1 and A induces proinflammatory responses through the migration and activation of monocytes in humans. While the SEC receptor mediates the internalization of A in neuronal cells, FPRL1 is involved in A internalization in macrophages, binding and internalizing A, and accumulating the fibrils form (Yazawa et al., 2001).
Page 39 of 68
8. Other amyloidogenic proteins Some amyloidogenic proteins are tightly involved in protein aggregation disorders, including transthyretin, -synuclein and A. Interestingly, they interact with each other and affect protein aggregation status, which has an impact on pathophysiology of disease progression.
ip t
Cross-seeding or cross-inhibition of aggregation is one of those outcomes for mutual
cr
interactions between amyloidogenic proteins, which is crucial to understand the neuropathological comorbidity of several neurodegenerative disorders.
us
8.1 Alpha-Synuclein
Sharing some clinical and pathophysiological features has raised the possibility of molecular
an
link between A and -synuclein, the main pathological hallmarks in AD and Parkinson’s
M
disease (PD) respectively. AD environment accelerate the formation of -synuclein fibril, proved by the effect of the CSF obtained from different neurological diseases including AD
d
(Ono et al., 2007). In doubly transgenic mice of human A peptides and -synuclein, A
Ac ce pt e
enhances -synuclein accumulation, fibril formation, and furthermore neuronal deficits (Masliah et al., 2001). In the other way, in vivo study using transgenic mice demonstrates that neurodegeneration induced by -synuclein alters ubiquitin/proteasome system, increases ApoE levels and A accumulation (Gallardo et al., 2008). A, tau and -synuclein appear to interact each other and enhance the accumulation and aggregation mutually which aggravate the cognitive dysfunction in 3XTg AD mice with mutant human -synuclein transgene (Clinton et al., 2010). Direct interaction between A and -synuclein was proved by in vitro multidimensional NMR spectroscopy study and in vivo study of brains from AD/PD patient and transgenic mice, which may be the possible pathophysiological mechanism of dementia with Lewy body disease (Mandal et al., 2006; Tsigelny et al., 2008). Cross-seeding effect has been confirmed after direct interaction between A and -synuclein (Ono et al., 2012) and this process is suspected as the molecular mechanisms contributing neuropathology. However,
Page 40 of 68
the seeming conflicting results propose that -synuclein plays a role not in cross-seeding of A plaques, but in inhibiting A plaque formation in vivo (Bachhuber et al., 2015). Significant increase of forebrain A plaque load is caused by loss of -synuclein in APP transgenic mice, which also support the idea that -synuclein is not associated with cross-
ip t
seeding of A aggregation (Kallhoff et al., 2007). In spites of these discrepancies,
cr
understanding of molecular relationship between -synuclein and A would be critical to develop effective treatment for PD and AD.
us
8.2 A40 and A42
Numerous isoforms of A peptides have properties to interact with each other. Specially,
an
A40 and A42 are in the center of interest because their interacting patterns and aggregating
M
status are tightly related to pathogenesis of AD. A40 interacts with A42 and affects propensity of aggregation, inhibiting A42 oligomerization, aggregation and amyloid
d
deposition (Kim et al., 2007; Murray et al., 2009; Yan and Wang, 2007). A40 interacts to
Ac ce pt e
A42 in concentration and ratio-dependent manner, changes the solubility, stability and morphological characteristics of A42 aggregates and finally inhibits the further maturation into fibrillization according to the ratio of A40 to A42 (Jan et al., 2008). Equilibrium point of the amyloid peptides has been suggested to be dependent upon the A40/A42 ratio and implicated in pathogenesis of AD. Besides affecting A42 aggregation pattern, A40-bound A42 oligomers are less toxic than A42 alone oligomers, reducing the toxicity on synapse including synaptic vesicle recycling and synaptophysin level (Bate and Williams, 2010). The possible mechanism for this less toxicity is the alleviation of cytoplasmic phospholipase A2 activation induced by A42 in synapse (Bate and Williams, 2010). BRI2 protein is type2 transmembrane protein with 266 amino acids and the two mutations in the ITM2b gene encoding BRI2 is responsible for familial British and Danish dementias which are neurodegenerative dementia characterized by neuronal loss, amyloid deposits, neurofibrillary
Page 41 of 68
tangles and cerebral amyloid angiopathy (Ghiso et al., 2006). Similar to the beneficial effect of A40, wild-type human BRI2 expression is reported to decrease A deposit in AD mouse model and bri23 released BRI2 prevents A aggregation in vitro which may mediate the antiamyloidogenic effect in vivo (Kim et al., 2008).
ip t
8.3 Transthyretin
cr
Transthyretin modulates A deposition by direct interaction and co-localizes in plaques with A (Buxbaum et al., 2008). Overexpression of human transthyretin was ameliorative while
us
the removals of transthyretin expression in diverse transgenic animal models aggravate the neuropathological phenotype caused by A, which suggest that transthyretin is protective by
an
binding to A aggregates in intracellular and extracellular compartment (Buxbaum et al.,
M
2008; Choi et al., 2007). However, in spite of beneficial effect of transthyretin to A pathology, transthyretin has no effect on reduction of A deposition, rather accelerate total
Ac ce pt e
d
and vascular A deposition in the mouse model of AD (Wati et al., 2009).
9. Conclusion
A-interacting molecules influence the etiology of AD, and may become useful indicative biomarkers or therapeutic targets following alterations in their expression levels in the brain or periphery. To date, multiple clinical trials targeting A resulted in disappointing failures. Therefore, researchers have realized that A is likely not the sole cause of AD, and have sought alternative therapeutic approaches. A-interacting molecules have attracted much attention based on their association with the predominant etiological factor A. Beneficial effects of the modulation of A-interacting partners during AD pathogenesis and disease progression have further expanded the fields of clinical application for possible AD therapeutics (Table 1). Specially, peripheral blood is a dynamic environment reflecting diverse changes in molecular and cellular functions in different regions of the body. Plasma
Page 42 of 68
levels of A-interacting proteins change during AD pathogenesis, and these alterations dependent on disease progression may provide critical information as diagnostic and surrogate biomarker. Also, multiple forms of A elicit diverse effects on intracellular organelles, neurons and synapses through binding to cellular, membrane and other effector
ip t
proteins. Thus, perturbation of these events may be the primary step to prevent the initiation
cr
or progression of AD and further utilized in therapeutic strategy. Investigation of specific A binding sites in A-interacting proteins would be helpful to inhibit or enhance interactions,
us
depending on the beneficial or deleterious effects resulted from these interactions. Further binding affinity studies for molecular structure modification may provide a better
an
understanding and discovery of effective binding competitors might open promising avenues
M
for the future development of AD therapeutic drugs modified from specific A-interacting
d
molecules.
This
Ac ce pt e
Acknowledgement work
was
supported
by
grants
from
NRF
(2015R1A2A1A05001794,
2014M3C7A1046047, 2015M3C7A1028790 and MRC (2012R1A5A2A44671346)) for I.MJ.
Page 43 of 68
References
Ac ce pt e
d
M
an
us
cr
ip t
Adlard, P. A., Parncutt, J. M., Finkelstein, D. I. and Bush, A. I. (2010) Cognitive loss in zinc transporter-3 knock-out mice: a phenocopy for the synaptic and memory deficits of Alzheimer's disease? The Journal of neuroscience : the official journal of the Society for Neuroscience 30, 1631-1636. Aicardi, G. (2013) New hope from an old drug: fighting Alzheimer's disease with the cancer drug bexarotene (targretin)? Rejuvenation research 16, 524-528. Akira, S. (2001) Toll-like receptors and innate immunity. Advances in immunology 78, 1-56. Aleshkov, S., Abraham, C. R. and Zannis, V. I. (1997) Interaction of nascent ApoE2, ApoE3, and ApoE4 isoforms expressed in mammalian cells with amyloid peptide beta (1-40). Relevance to Alzheimer's disease. Biochemistry 36, 10571-10580. Alier, K., Ma, L., Yang, J., Westaway, D. and Jhamandas, J. H. (2011) Abeta inhibition of ionic conductance in mouse basal forebrain neurons is dependent upon the cellular prion protein PrPC. The Journal of neuroscience : the official journal of the Society for Neuroscience 31, 16292-16297. Alikhani, N., Guo, L., Yan, S., Du, H., Pinho, C. M., Chen, J. X., Glaser, E. and Yan, S. S. (2011) Decreased proteolytic activity of the mitochondrial amyloid-beta degrading enzyme, PreP peptidasome, in Alzheimer's disease brain mitochondria. Journal of Alzheimer's disease : JAD 27, 75-87. Andreeva, L., Heads, R. and Green, C. J. (1999) Cyclophilins and their possible role in the stress response. International journal of experimental pathology 80, 305-315. Arancio, O., Zhang, H. P., Chen, X., Lin, C., Trinchese, F., Puzzo, D., Liu, S., Hegde, A., Yan, S. F., Stern, A., Luddy, J. S., Lue, L. F., Walker, D. G., Roher, A., Buttini, M., Mucke, L., Li, W., Schmidt, A. M., Kindy, M., Hyslop, P. A., Stern, D. M. and Du Yan, S. S. (2004) RAGE potentiates Abeta-induced perturbation of neuronal function in transgenic mice. The EMBO journal 23, 4096-4105. Aronow, B. J., Lund, S. D., Brown, T. L., Harmony, J. A. and Witte, D. P. (1993) Apolipoprotein J expression at fluid-tissue interfaces: potential role in barrier cytoprotection. Proceedings of the National Academy of Sciences of the United States of America 90, 725-729. Atwal, J. K., Pinkston-Gosse, J., Syken, J., Stawicki, S., Wu, Y., Shatz, C. and Tessier-Lavigne, M. (2008) PirB is a functional receptor for myelin inhibitors of axonal regeneration. Science 322, 967-970. Atwood, C. S., Moir, R. D., Huang, X., Scarpa, R. C., Bacarra, N. M., Romano, D. M., Hartshorn, M. A., Tanzi, R. E. and Bush, A. I. (1998) Dramatic aggregation of Alzheimer abeta by Cu(II) is induced by conditions representing physiological acidosis. The Journal of biological chemistry 273, 12817-12826. Bachhuber, T., Katzmarski, N., McCarter, J. F., Loreth, D., Tahirovic, S., Kamp, F., Abou-Ajram, C., Nuscher, B., Serrano-Pozo, A., Muller, A., Prinz, M., Steiner, H., Hyman, B. T., Haass, C. and Meyer-Luehmann, M. (2015) Inhibition of amyloid-beta plaque formation by alpha-synuclein. Nature medicine 21, 802807. Bales, K. R., Verina, T., Dodel, R. C., Du, Y., Altstiel, L., Bender, M., Hyslop, P., Johnstone, E. M., Little, S. P., Cummins, D. J., Piccardo, P., Ghetti, B. and Paul, S. M. (1997) Lack of apolipoprotein E dramatically reduces amyloid beta-peptide deposition. Nature genetics 17, 263-264. Bamberger, M. E., Harris, M. E., McDonald, D. R., Husemann, J. and Landreth, G. E. (2003) A cell surface receptor complex for fibrillar beta-amyloid mediates microglial activation. The Journal of neuroscience : the official journal of the Society for Neuroscience 23, 2665-2674. Banks, W. A., Maness, L. M., Banks, M. F. and Kastin, A. J. (1996) Aluminum-sensitive degradation of amyloid beta-protein 1-40 by murine and human intracellular enzymes. Neurotoxicology and teratology 18, 671-677. Basak, J. M., Verghese, P. B., Yoon, H., Kim, J. and Holtzman, D. M. (2012) Low-density lipoprotein receptor represents an apolipoprotein E-independent pathway of Abeta uptake and degradation by astrocytes. The Journal of biological chemistry 287, 13959-13971. Basso, E., Fante, L., Fowlkes, J., Petronilli, V., Forte, M. A. and Bernardi, P. (2005) Properties of the permeability transition pore in mitochondria devoid of Cyclophilin D. The Journal of biological chemistry 280, 18558-18561. Bate, C. and Williams, A. (2010) Amyloid-beta(1-40) inhibits amyloid-beta(1-42) induced activation of cytoplasmic phospholipase A2 and synapse degeneration. Journal of Alzheimer's disease : JAD 21, 985-993. Bate, C. and Williams, A. (2011) Amyloid-beta-induced synapse damage is mediated via cross-linkage of cellular prion proteins. The Journal of biological chemistry 286, 37955-37963. Baumann, C. L., Aspalter, I. M., Sharif, O., Pichlmair, A., Bluml, S., Grebien, F., Bruckner, M., Pasierbek, P., Aumayr, K., Planyavsky, M., Bennett, K. L., Colinge, J., Knapp, S. and Superti-Furga, G. (2010) CD14 is a coreceptor of Toll-like receptors 7 and 9. The Journal of experimental medicine 207, 2689-2701. Bayer, T. A., Schafer, S., Simons, A., Kemmling, A., Kamer, T., Tepest, R., Eckert, A., Schussel, K., Eikenberg,
Page 44 of 68
Ac ce pt e
d
M
an
us
cr
ip t
O., Sturchler-Pierrat, C., Abramowski, D., Staufenbiel, M. and Multhaup, G. (2003) Dietary Cu stabilizes brain superoxide dismutase 1 activity and reduces amyloid Abeta production in APP23 transgenic mice. Proceedings of the National Academy of Sciences of the United States of America 100, 14187-14192. Benilova, I. and De Strooper, B. (2013) Neuroscience. Promiscuous Alzheimer's amyloid: yet another partner. Science 341, 1354-1355. Bi, X., Gall, C. M., Zhou, J. and Lynch, G. (2002) Uptake and pathogenic effects of amyloid beta peptide 1-42 are enhanced by integrin antagonists and blocked by NMDA receptor antagonists. Neuroscience 112, 827-840. Bianchi, R., Adami, C., Giambanco, I. and Donato, R. (2007) S100B binding to RAGE in microglia stimulates COX-2 expression. Journal of leukocyte biology 81, 108-118. Bien-Ly, N., Gillespie, A. K., Walker, D., Yoon, S. Y. and Huang, Y. (2012) Reducing human apolipoprotein E levels attenuates age-dependent Abeta accumulation in mutant human amyloid precursor protein transgenic mice. The Journal of neuroscience : the official journal of the Society for Neuroscience 32, 4803-4811. Biere, A. L., Ostaszewski, B., Stimson, E. R., Hyman, B. T., Maggio, J. E. and Selkoe, D. J. (1996) Amyloid beta-peptide is transported on lipoproteins and albumin in human plasma. The Journal of biological chemistry 271, 32916-32922. Blacker, D., Wilcox, M. A., Laird, N. M., Rodes, L., Horvath, S. M., Go, R. C., Perry, R., Watson, B., Jr., Bassett, S. S., McInnis, M. G., Albert, M. S., Hyman, B. T. and Tanzi, R. E. (1998) Alpha-2 macroglobulin is genetically associated with Alzheimer disease. Nature genetics 19, 357-360. Boada, M., Ortiz, P., Anaya, F., Hernandez, I., Munoz, J., Nunez, L., Olazaran, J., Roca, I., Cuberas, G., Tarraga, L., Buendia, M., Pla, R. P., Ferrer, I. and Paez, A. (2009) Amyloid-targeted therapeutics in Alzheimer's disease: use of human albumin in plasma exchange as a novel approach for Abeta mobilization. Drug news & perspectives 22, 325-339. Bohrmann, B., Tjernberg, L., Kuner, P., Poli, S., Levet-Trafit, B., Naslund, J., Richards, G., Huber, W., Dobeli, H. and Nordstedt, C. (1999) Endogenous proteins controlling amyloid beta-peptide polymerization. Possible implications for beta-amyloid formation in the central nervous system and in peripheral tissues. The Journal of biological chemistry 274, 15990-15995. Boland, K., Behrens, M., Choi, D., Manias, K. and Perlmutter, D. H. (1996) The serpin-enzyme complex receptor recognizes soluble, nontoxic amyloid-beta peptide but not aggregated, cytotoxic amyloid-beta peptide. The Journal of biological chemistry 271, 18032-18044. Boland, K., Manias, K. and Perlmutter, D. H. (1995) Specificity in recognition of amyloid-beta peptide by the serpin-enzyme complex receptor in hepatoma cells and neuronal cells. The Journal of biological chemistry 270, 28022-28028. Bousejra-ElGarah, F., Bijani, C., Coppel, Y., Faller, P. and Hureau, C. (2011) Iron(II) binding to amyloid-beta, the Alzheimer's peptide. Inorganic chemistry 50, 9024-9030. Breen, K. C., Bruce, M. and Anderton, B. H. (1991) Beta amyloid precursor protein mediates neuronal cell-cell and cell-surface adhesion. Journal of neuroscience research 28, 90-100. Breese, C. R., Adams, C., Logel, J., Drebing, C., Rollins, Y., Barnhart, M., Sullivan, B., Demasters, B. K., Freedman, R. and Leonard, S. (1997) Comparison of the regional expression of nicotinic acetylcholine receptor alpha7 mRNA and [125I]-alpha-bungarotoxin binding in human postmortem brain. The Journal of comparative neurology 387, 385-398. Brewer, G. J., Kanzer, S. H., Zimmerman, E. A., Celmins, D. F., Heckman, S. M. and Dick, R. (2010) Copper and ceruloplasmin abnormalities in Alzheimer's disease. American journal of Alzheimer's disease and other dementias 25, 490-497. Bu, G., Maksymovitch, E. A., Nerbonne, J. M. and Schwartz, A. L. (1994) Expression and function of the low density lipoprotein receptor-related protein (LRP) in mammalian central neurons. The Journal of biological chemistry 269, 18521-18528. Burstein, A. H., Grimes, I., Galasko, D. R., Aisen, P. S., Sabbagh, M. and Mjalli, A. M. (2014) Effect of TTP488 in patients with mild to moderate Alzheimer's disease. BMC neurology 14, 12. Bush, A. I. (2013) The metal theory of Alzheimer's disease. Journal of Alzheimer's disease : JAD 33 Suppl 1, S277-281. Buttini, M., Yu, G. Q., Shockley, K., Huang, Y., Jones, B., Masliah, E., Mallory, M., Yeo, T., Longo, F. M. and Mucke, L. (2002) Modulation of Alzheimer-like synaptic and cholinergic deficits in transgenic mice by human apolipoprotein E depends on isoform, aging, and overexpression of amyloid beta peptides but not on plaque formation. The Journal of neuroscience : the official journal of the Society for Neuroscience 22, 10539-10548. Buxbaum, J. N., Ye, Z., Reixach, N., Friske, L., Levy, C., Das, P., Golde, T., Masliah, E., Roberts, A. R. and
Page 45 of 68
Ac ce pt e
d
M
an
us
cr
ip t
Bartfai, T. (2008) Transthyretin protects Alzheimer's mice from the behavioral and biochemical effects of Abeta toxicity. Proceedings of the National Academy of Sciences of the United States of America 105, 2681-2686. Calero, M., Rostagno, A., Matsubara, E., Zlokovic, B., Frangione, B. and Ghiso, J. (2000) Apolipoprotein J (clusterin) and Alzheimer's disease. Microscopy research and technique 50, 305-315. Campbell, A., Kumar, A., La Rosa, F. G., Prasad, K. N. and Bondy, S. C. (2000) Aluminum increases levels of beta-amyloid and ubiquitin in neuroblastoma but not in glioma cells. Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine 223, 397-402. Canevari, L., Abramov, A. Y. and Duchen, M. R. (2004) Toxicity of amyloid beta peptide: tales of calcium, mitochondria, and oxidative stress. Neurochemical research 29, 637-650. Canton, J., Neculai, D. and Grinstein, S. (2013) Scavenger receptors in homeostasis and immunity. Nature reviews. Immunology 13, 621-634. Carter, D. C. and Ho, J. X. (1994) Structure of serum albumin. Advances in protein chemistry 45, 153-203. Casley, C. S., Canevari, L., Land, J. M., Clark, J. B. and Sharpe, M. A. (2002) Beta-amyloid inhibits integrated mitochondrial respiration and key enzyme activities. Journal of neurochemistry 80, 91-100. Castano, E. M., Prelli, F., Wisniewski, T., Golabek, A., Kumar, R. A., Soto, C. and Frangione, B. (1995) Fibrillogenesis in Alzheimer's disease of amyloid beta peptides and apolipoprotein E. The Biochemical journal 306 ( Pt 2), 599-604. Castano, E. M., Roher, A. E., Esh, C. L., Kokjohn, T. A. and Beach, T. (2006) Comparative proteomics of cerebrospinal fluid in neuropathologically-confirmed Alzheimer's disease and non-demented elderly subjects. Neurological research 28, 155-163. Cedazo-Minguez, A., Wiehager, B., Winblad, B., Huttinger, M. and Cowburn, R. F. (2001) Effects of apolipoprotein E (apoE) isoforms, beta-amyloid (Abeta) and apoE/Abeta complexes on protein kinase C-alpha (PKC-alpha) translocation and amyloid precursor protein (APP) processing in human SHSY5Y neuroblastoma cells and fibroblasts. Neurochemistry international 38, 615-625. Cha, M. Y., Cho, H. J., Kim, C., Jung, Y. O., Kang, M. J., Murray, M. E., Hong, H. S., Choi, Y. J., Choi, H., Kim, D. K., Choi, H., Kim, J., Dickson, D. W., Song, H. K., Cho, J. W., Yi, E. C., Kim, J., Jin, S. M. and Mook-Jung, I. (2015) Mitochondrial ATP synthase activity is impaired by suppressed O-GlcNAcylation in Alzheimer's disease. Human molecular genetics 24, 6492-6504. Cha, M. Y., Han, S. H., Son, S. M., Hong, H. S., Choi, Y. J., Byun, J. and Mook-Jung, I. (2012) Mitochondriaspecific accumulation of amyloid beta induces mitochondrial dysfunction leading to apoptotic cell death. PloS one 7, e34929. Chappell, D. A., Fry, G. L., Waknitz, M. A., Iverius, P. H., Williams, S. E. and Strickland, D. K. (1992) The low density lipoprotein receptor-related protein/alpha 2-macroglobulin receptor binds and mediates catabolism of bovine milk lipoprotein lipase. The Journal of biological chemistry 267, 25764-25767. Chen, J. X. and Yan, S. D. (2007) Amyloid-beta-induced mitochondrial dysfunction. Journal of Alzheimer's disease : JAD 12, 177-184. Chen, K., Iribarren, P., Hu, J., Chen, J., Gong, W., Cho, E. H., Lockett, S., Dunlop, N. M. and Wang, J. M. (2006) Activation of Toll-like receptor 2 on microglia promotes cell uptake of Alzheimer disease-associated amyloid beta peptide. The Journal of biological chemistry 281, 3651-3659. Cherny, R. A., Atwood, C. S., Xilinas, M. E., Gray, D. N., Jones, W. D., McLean, C. A., Barnham, K. J., Volitakis, I., Fraser, F. W., Kim, Y., Huang, X., Goldstein, L. E., Moir, R. D., Lim, J. T., Beyreuther, K., Zheng, H., Tanzi, R. E., Masters, C. L. and Bush, A. I. (2001) Treatment with a copper-zinc chelator markedly and rapidly inhibits beta-amyloid accumulation in Alzheimer's disease transgenic mice. Neuron 30, 665-676. Cho, H. J., Son, S. M., Jin, S. M., Hong, H. S., Shin, D. H., Kim, S. J., Huh, K. and Mook-Jung, I. (2009) RAGE regulates BACE1 and Abeta generation via NFAT1 activation in Alzheimer's disease animal model. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 23, 2639-2649. Choi, B. R., Cho, W. H., Kim, J., Lee, H. J., Chung, C., Jeon, W. K. and Han, J. S. (2014) Increased expression of the receptor for advanced glycation end products in neurons and astrocytes in a triple transgenic mouse model of Alzheimer's disease. Experimental & molecular medicine 46, e75. Choi, S. H., Leight, S. N., Lee, V. M., Li, T., Wong, P. C., Johnson, J. A., Saraiva, M. J. and Sisodia, S. S. (2007) Accelerated Abeta deposition in APPswe/PS1deltaE9 mice with hemizygous deletions of TTR (transthyretin). The Journal of neuroscience : the official journal of the Society for Neuroscience 27, 7006-7010. Chung, E., Ji, Y., Sun, Y., Kascsak, R. J., Kascsak, R. B., Mehta, P. D., Strittmatter, S. M. and Wisniewski, T. (2010) Anti-PrPC monoclonal antibody infusion as a novel treatment for cognitive deficits in an Alzheimer's disease model mouse. BMC neuroscience 11, 130.
Page 46 of 68
Ac ce pt e
d
M
an
us
cr
ip t
Cisse, M., Halabisky, B., Harris, J., Devidze, N., Dubal, D. B., Sun, B., Orr, A., Lotz, G., Kim, D. H., Hamto, P., Ho, K., Yu, G. Q. and Mucke, L. (2011) Reversing EphB2 depletion rescues cognitive functions in Alzheimer model. Nature 469, 47-52. Clauberg, M. and Joshi, J. G. (1993) Regulation of serine protease activity by aluminum: implications for Alzheimer disease. Proceedings of the National Academy of Sciences of the United States of America 90, 1009-1012. Clinton, L. K., Blurton-Jones, M., Myczek, K., Trojanowski, J. Q. and LaFerla, F. M. (2010) Synergistic Interactions between Abeta, tau, and alpha-synuclein: acceleration of neuropathology and cognitive decline. The Journal of neuroscience : the official journal of the Society for Neuroscience 30, 72817289. Colombini, M. (2012) VDAC structure, selectivity, and dynamics. Biochimica et biophysica acta 1818, 14571465. Combs, C. K., Johnson, D. E., Cannady, S. B., Lehman, T. M. and Landreth, G. E. (1999) Identification of microglial signal transduction pathways mediating a neurotoxic response to amyloidogenic fragments of beta-amyloid and prion proteins. The Journal of neuroscience : the official journal of the Society for Neuroscience 19, 928-939. Connern, C. P. and Halestrap, A. P. (1994) Recruitment of mitochondrial cyclophilin to the mitochondrial inner membrane under conditions of oxidative stress that enhance the opening of a calcium-sensitive nonspecific channel. The Biochemical journal 302 ( Pt 2), 321-324. Costa, M., Ortiz, A. M. and Jorquera, J. I. (2012) Therapeutic albumin binding to remove amyloid-beta. Journal of Alzheimer's disease : JAD 29, 159-170. Costa, R., Ferreira-da-Silva, F., Saraiva, M. J. and Cardoso, I. (2008) Transthyretin protects against A-beta peptide toxicity by proteolytic cleavage of the peptide: a mechanism sensitive to the Kunitz protease inhibitor. PloS one 3, e2899. Cramer, P. E., Cirrito, J. R., Wesson, D. W., Lee, C. Y., Karlo, J. C., Zinn, A. E., Casali, B. T., Restivo, J. L., Goebel, W. D., James, M. J., Brunden, K. R., Wilson, D. A. and Landreth, G. E. (2012) ApoE-directed therapeutics rapidly clear beta-amyloid and reverse deficits in AD mouse models. Science 335, 15031506. Crouch, P. J. and Barnham, K. J. (2012) Therapeutic redistribution of metal ions to treat Alzheimer's disease. Accounts of chemical research 45, 1604-1611. Cuajungco, M. P. and Faget, K. Y. (2003) Zinc takes the center stage: its paradoxical role in Alzheimer's disease. Brain research. Brain research reviews 41, 44-56. Curtain, C. C., Ali, F. E., Smith, D. G., Bush, A. I., Masters, C. L. and Barnham, K. J. (2003) Metal ions, pH, and cholesterol regulate the interactions of Alzheimer's disease amyloid-beta peptide with membrane lipid. The Journal of biological chemistry 278, 2977-2982. Dai, W., Yang, J., Chen, T. and Yang, Z. (2014) Protective Effects of Bexarotene against Amyloid-beta-Induced Dysfunction in Hippocampal Neurons through the Insulin Signaling Pathway. Neuro-degenerative diseases. Danscher, G., Jensen, K. B., Frederickson, C. J., Kemp, K., Andreasen, A., Juhl, S., Stoltenberg, M. and Ravid, R. (1997) Increased amount of zinc in the hippocampus and amygdala of Alzheimer's diseased brains: a proton-induced X-ray emission spectroscopic analysis of cryostat sections from autopsy material. Journal of neuroscience methods 76, 53-59. Danysz, W. and Parsons, C. G. (2012) Alzheimer's disease, beta-amyloid, glutamate, NMDA receptors and memantine--searching for the connections. British journal of pharmacology 167, 324-352. Das, P., Kang, S. G., Temple, S. and Belfort, G. (2014) Interaction of amyloid inhibitor proteins with amyloid beta peptides: insight from molecular dynamics simulations. PloS one 9, e113041. de Arriba, S. G., Loske, C., Meiners, I., Fleischer, G., Lobisch, M., Wessel, K., Tritschler, H., Schinzel, R. and Munch, G. (2003) Advanced glycation endproducts induce changes in glucose consumption, lactate production, and ATP levels in SH-SY5Y neuroblastoma cells by a redox-sensitive mechanism. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 23, 1307-1313. de Silva, H. V., Harmony, J. A., Stuart, W. D., Gil, C. M. and Robbins, J. (1990) Apolipoprotein J: structure and tissue distribution. Biochemistry 29, 5380-5389. Deane, R., Du Yan, S., Submamaryan, R. K., LaRue, B., Jovanovic, S., Hogg, E., Welch, D., Manness, L., Lin, C., Yu, J., Zhu, H., Ghiso, J., Frangione, B., Stern, A., Schmidt, A. M., Armstrong, D. L., Arnold, B., Liliensiek, B., Nawroth, P., Hofman, F., Kindy, M., Stern, D. and Zlokovic, B. (2003) RAGE mediates amyloid-beta peptide transport across the blood-brain barrier and accumulation in brain. Nature medicine 9, 907-913. Deane, R., Singh, I., Sagare, A. P., Bell, R. D., Ross, N. T., LaRue, B., Love, R., Perry, S., Paquette, N., Deane,
Page 47 of 68
Ac ce pt e
d
M
an
us
cr
ip t
R. J., Thiyagarajan, M., Zarcone, T., Fritz, G., Friedman, A. E., Miller, B. L. and Zlokovic, B. V. (2012) A multimodal RAGE-specific inhibitor reduces amyloid beta-mediated brain disorder in a mouse model of Alzheimer disease. The Journal of clinical investigation 122, 1377-1392. Deane, R., Wu, Z., Sagare, A., Davis, J., Du Yan, S., Hamm, K., Xu, F., Parisi, M., LaRue, B., Hu, H. W., Spijkers, P., Guo, H., Song, X., Lenting, P. J., Van Nostrand, W. E. and Zlokovic, B. V. (2004) LRP/amyloid beta-peptide interaction mediates differential brain efflux of Abeta isoforms. Neuron 43, 333-344. Deane, R. and Zlokovic, B. V. (2007) Role of the blood-brain barrier in the pathogenesis of Alzheimer's disease. Current Alzheimer research 4, 191-197. Deibel, M. A., Ehmann, W. D. and Markesbery, W. R. (1996) Copper, iron, and zinc imbalances in severely degenerated brain regions in Alzheimer's disease: possible relation to oxidative stress. Journal of the neurological sciences 143, 137-142. Diarra, A., Geetha, T., Potter, P. and Babu, J. R. (2009) Signaling of the neurotrophin receptor p75 in relation to Alzheimer's disease. Biochemical and biophysical research communications 390, 352-356. Dinamarca, M. C., Rios, J. A. and Inestrosa, N. C. (2012) Postsynaptic Receptors for Amyloid-beta Oligomers as Mediators of Neuronal Damage in Alzheimer's Disease. Frontiers in physiology 3, 464. Donahue, J. E., Flaherty, S. L., Johanson, C. E., Duncan, J. A., 3rd, Silverberg, G. D., Miller, M. C., Tavares, R., Yang, W., Wu, Q., Sabo, E., Hovanesian, V. and Stopa, E. G. (2006) RAGE, LRP-1, and amyloid-beta protein in Alzheimer's disease. Acta neuropathologica 112, 405-415. Dougherty, J. J., Wu, J. and Nichols, R. A. (2003) Beta-amyloid regulation of presynaptic nicotinic receptors in rat hippocampus and neocortex. The Journal of neuroscience : the official journal of the Society for Neuroscience 23, 6740-6747. Du, H., Guo, L., Fang, F., Chen, D., Sosunov, A. A., McKhann, G. M., Yan, Y., Wang, C., Zhang, H., Molkentin, J. D., Gunn-Moore, F. J., Vonsattel, J. P., Arancio, O., Chen, J. X. and Yan, S. D. (2008) Cyclophilin D deficiency attenuates mitochondrial and neuronal perturbation and ameliorates learning and memory in Alzheimer's disease. Nature medicine 14, 1097-1105. Du, H., Guo, L., Zhang, W., Rydzewska, M. and Yan, S. (2011) Cyclophilin D deficiency improves mitochondrial function and learning/memory in aging Alzheimer disease mouse model. Neurobiology of aging 32, 398-406. Du, J., Cho, P. Y., Yang, D. T. and Murphy, R. M. (2012) Identification of beta-amyloid-binding sites on transthyretin. Protein engineering, design & selection : PEDS 25, 337-345. Du, Y., Ni, B., Glinn, M., Dodel, R. C., Bales, K. R., Zhang, Z., Hyslop, P. A. and Paul, S. M. (1997) alpha2Macroglobulin as a beta-amyloid peptide-binding plasma protein. Journal of neurochemistry 69, 299305. Duce, J. A., Tsatsanis, A., Cater, M. A., James, S. A., Robb, E., Wikhe, K., Leong, S. L., Perez, K., Johanssen, T., Greenough, M. A., Cho, H. H., Galatis, D., Moir, R. D., Masters, C. L., McLean, C., Tanzi, R. E., Cappai, R., Barnham, K. J., Ciccotosto, G. D., Rogers, J. T. and Bush, A. I. (2010) Iron-export ferroxidase activity of beta-amyloid precursor protein is inhibited by zinc in Alzheimer's disease. Cell 142, 857-867. Duguid, J. R., Bohmont, C. W., Liu, N. G. and Tourtellotte, W. W. (1989) Changes in brain gene expression shared by scrapie and Alzheimer disease. Proceedings of the National Academy of Sciences of the United States of America 86, 7260-7264. El Khoury, J., Hickman, S. E., Thomas, C. A., Cao, L., Silverstein, S. C. and Loike, J. D. (1996) Scavenger receptor-mediated adhesion of microglia to beta-amyloid fibrils. Nature 382, 716-719. Eriksson, S., Janciauskiene, S. and Lannfelt, L. (1995) Alpha 1-antichymotrypsin regulates Alzheimer betaamyloid peptide fibril formation. Proceedings of the National Academy of Sciences of the United States of America 92, 2313-2317. Exley, C. (2005) The aluminium-amyloid cascade hypothesis and Alzheimer's disease. Sub-cellular biochemistry 38, 225-234. Exley, C. (2006) Aluminium and iron, but neither copper nor zinc, are key to the precipitation of beta-sheets of Abeta_{42} in senile plaque cores in Alzheimer's disease. Journal of Alzheimer's disease : JAD 10, 173-177. Exley, C. and Korchazhkina, O. V. (2001) Promotion of formation of amyloid fibrils by aluminium adenosine triphosphate (AlATP). Journal of inorganic biochemistry 84, 215-224. Exley, C., Price, N. C., Kelly, S. M. and Birchall, J. D. (1993) An interaction of beta-amyloid with aluminium in vitro. FEBS letters 324, 293-295. Fagan, A. M., Watson, M., Parsadanian, M., Bales, K. R., Paul, S. M. and Holtzman, D. M. (2002) Human and murine ApoE markedly alters A beta metabolism before and after plaque formation in a mouse model of Alzheimer's disease. Neurobiology of disease 9, 305-318.
Page 48 of 68
Ac ce pt e
d
M
an
us
cr
ip t
Falkevall, A., Alikhani, N., Bhushan, S., Pavlov, P. F., Busch, K., Johnson, K. A., Eneqvist, T., Tjernberg, L., Ankarcrona, M. and Glaser, E. (2006) Degradation of the amyloid beta-protein by the novel mitochondrial peptidasome, PreP. The Journal of biological chemistry 281, 29096-29104. Faller, P. (2009) Copper and zinc binding to amyloid-beta: coordination, dynamics, aggregation, reactivity and metal-ion transfer. Chembiochem : a European journal of chemical biology 10, 2837-2845. Fang, F., Lue, L. F., Yan, S., Xu, H., Luddy, J. S., Chen, D., Walker, D. G., Stern, D. M., Yan, S., Schmidt, A. M., Chen, J. X. and Yan, S. S. (2010) RAGE-dependent signaling in microglia contributes to neuroinflammation, Abeta accumulation, and impaired learning/memory in a mouse model of Alzheimer's disease. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 24, 1043-1055. Faux, N. G., Ritchie, C. W., Gunn, A., Rembach, A., Tsatsanis, A., Bedo, J., Harrison, J., Lannfelt, L., Blennow, K., Zetterberg, H., Ingelsson, M., Masters, C. L., Tanzi, R. E., Cummings, J. L., Herd, C. M. and Bush, A. I. (2010) PBT2 rapidly improves cognition in Alzheimer's Disease: additional phase II analyses. Journal of Alzheimer's disease : JAD 20, 509-516. Fonte, V., Kapulkin, W. J., Taft, A., Fluet, A., Friedman, D. and Link, C. D. (2002) Interaction of intracellular beta amyloid peptide with chaperone proteins. Proceedings of the National Academy of Sciences of the United States of America 99, 9439-9444. Freir, D. B., Nicoll, A. J., Klyubin, I., Panico, S., Mc Donald, J. M., Risse, E., Asante, E. A., Farrow, M. A., Sessions, R. B., Saibil, H. R., Clarke, A. R., Rowan, M. J., Walsh, D. M. and Collinge, J. (2011) Interaction between prion protein and toxic amyloid beta assemblies can be therapeutically targeted at multiple sites. Nature communications 2, 336. Fuentealba, R. A., Liu, Q., Zhang, J., Kanekiyo, T., Hu, X., Lee, J. M., LaDu, M. J. and Bu, G. (2010) Lowdensity lipoprotein receptor-related protein 1 (LRP1) mediates neuronal Abeta42 uptake and lysosomal trafficking. PloS one 5, e11884. Fukui, H., Diaz, F., Garcia, S. and Moraes, C. T. (2007) Cytochrome c oxidase deficiency in neurons decreases both oxidative stress and amyloid formation in a mouse model of Alzheimer's disease. Proceedings of the National Academy of Sciences of the United States of America 104, 14163-14168. Galasko, D., Bell, J., Mancuso, J. Y., Kupiec, J. W., Sabbagh, M. N., van Dyck, C., Thomas, R. G., Aisen, P. S. and Alzheimer's Disease Cooperative, S. (2014) Clinical trial of an inhibitor of RAGE-Abeta interactions in Alzheimer disease. Neurology 82, 1536-1542. Gallardo, G., Schluter, O. M. and Sudhof, T. C. (2008) A molecular pathway of neurodegeneration linking alpha-synuclein to ApoE and Abeta peptides. Nature neuroscience 11, 301-308. Gault, L. M., Ritchie, C. W., Robieson, W. Z., Pritchett, Y., Othman, A. A. and Lenz, R. A. (2015) A phase 2 randomized, controlled trial of the 7 agonist ABT-126 in mild-to-moderate Alzheimer's dementia. Alzheimer's & Dementia: Translational Research & Clinical Interventions 1, 81-90. Ghiso, J., Rostagno, A., Gardella, J. E., Liem, L., Gorevic, P. D. and Frangione, B. (1992) A 109-amino-acid Cterminal fragment of Alzheimer's-disease amyloid precursor protein contains a sequence, -RHDS-, that promotes cell adhesion. The Biochemical journal 288 ( Pt 3), 1053-1059. Ghiso, J., Rostagno, A., Tomidokoro, Y., Lashley, T., Bojsen-Moller, M., Braendgaard, H., Plant, G., Holton, J., Lal, R., Revesz, T. and Frangione, B. (2006) Genetic alterations of the BRI2 gene: familial British and Danish dementias. Brain pathology 16, 71-79. Gimbel, D. A., Nygaard, H. B., Coffey, E. E., Gunther, E. C., Lauren, J., Gimbel, Z. A. and Strittmatter, S. M. (2010) Memory impairment in transgenic Alzheimer mice requires cellular prion protein. The Journal of neuroscience : the official journal of the Society for Neuroscience 30, 6367-6374. Golabek, A., Marques, M. A., Lalowski, M. and Wisniewski, T. (1995) Amyloid beta binding proteins in vitro and in normal human cerebrospinal fluid. Neuroscience letters 191, 79-82. Gordon, S. (2002) Pattern recognition receptors: doubling up for the innate immune response. Cell 111, 927-930. Gouras, G. K., Tsai, J., Naslund, J., Vincent, B., Edgar, M., Checler, F., Greenfield, J. P., Haroutunian, V., Buxbaum, J. D., Xu, H., Greengard, P. and Relkin, N. R. (2000) Intraneuronal Abeta42 accumulation in human brain. The American journal of pathology 156, 15-20. Gupta, V. B., Laws, S. M., Villemagne, V. L., Ames, D., Bush, A. I., Ellis, K. A., Lui, J. K., Masters, C., Rowe, C. C., Szoeke, C., Taddei, K., Martins, R. N. and Group, A. R. (2011) Plasma apolipoprotein E and Alzheimer disease risk: the AIBL study of aging. Neurology 76, 1091-1098. Halestrap, A. P., McStay, G. P. and Clarke, S. J. (2002) The permeability transition pore complex: another view. Biochimie 84, 153-166. Hammad, S. M., Ranganathan, S., Loukinova, E., Twal, W. O. and Argraves, W. S. (1997) Interaction of apolipoprotein J-amyloid beta-peptide complex with low density lipoprotein receptor-related protein2/megalin. A mechanism to prevent pathological accumulation of amyloid beta-peptide. The Journal of biological chemistry 272, 18644-18649.
Page 49 of 68
Ac ce pt e
d
M
an
us
cr
ip t
Han, S. H., Jung, E. S., Sohn, J. H., Hong, H. J., Hong, H. S., Kim, J. W., Na, D. L., Kim, M., Kim, H., Ha, H. J., Kim, Y. H., Huh, N., Jung, M. W. and Mook-Jung, I. (2011a) Human serum transthyretin levels correlate inversely with Alzheimer's disease. Journal of Alzheimer's disease : JAD 25, 77-84. Han, S. H., Kim, J. S., Lee, Y., Choi, H., Kim, J. W., Na, D. L., Yang, E. G., Yu, M. H., Hwang, D., Lee, C. and Mook-Jung, I. (2014) Both targeted mass spectrometry and flow sorting analysis methods detected the decreased serum apolipoprotein e level in Alzheimer's disease patients. Molecular & cellular proteomics : MCP 13, 407-419. Han, S. H., Kim, Y. H. and Mook-Jung, I. (2011b) RAGE: the beneficial and deleterious effects by diverse mechanisms of actions. Molecules and cells 31, 91-97. Hansson, S. F., Andreasson, U., Wall, M., Skoog, I., Andreasen, N., Wallin, A., Zetterberg, H. and Blennow, K. (2009) Reduced levels of amyloid-beta-binding proteins in cerebrospinal fluid from Alzheimer's disease patients. Journal of Alzheimer's disease : JAD 16, 389-397. Henderson, J. T., Georgiou, J., Jia, Z., Robertson, J., Elowe, S., Roder, J. C. and Pawson, T. (2001) The receptor tyrosine kinase EphB2 regulates NMDA-dependent synaptic function. Neuron 32, 1041-1056. Henry-Mowatt, J., Dive, C., Martinou, J. C. and James, D. (2004) Role of mitochondrial membrane permeabilization in apoptosis and cancer. Oncogene 23, 2850-2860. Herber, D. L., Mercer, M., Roth, L. M., Symmonds, K., Maloney, J., Wilson, N., Freeman, M. J., Morgan, D. and Gordon, M. N. (2007) Microglial activation is required for Abeta clearance after intracranial injection of lipopolysaccharide in APP transgenic mice. Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology 2, 222-231. Hernandez-Zimbron, L. F., Luna-Munoz, J., Mena, R., Vazquez-Ramirez, R., Kubli-Garfias, C., Cribbs, D. H., Manoutcharian, K. and Gevorkian, G. (2012) Amyloid-beta peptide binds to cytochrome C oxidase subunit 1. PloS one 7, e42344. Herold, K., Moser, B., Chen, Y., Zeng, S., Yan, S. F., Ramasamy, R., Emond, J., Clynes, R. and Schmidt, A. M. (2007) Receptor for advanced glycation end products (RAGE) in a dash to the rescue: inflammatory signals gone awry in the primal response to stress. Journal of leukocyte biology 82, 204-212. Herz, J. and Marschang, P. (2003) Coaxing the LDL receptor family into the fold. Cell 112, 289-292. Herz, J. and Strickland, D. K. (2001) LRP: a multifunctional scavenger and signaling receptor. The Journal of clinical investigation 108, 779-784. Hesse, C., Larsson, H., Fredman, P., Minthon, L., Andreasen, N., Davidsson, P. and Blennow, K. (2000) Measurement of apolipoprotein E (apoE) in cerebrospinal fluid. Neurochemical research 25, 511-517. Hodge, T. and Colombini, M. (1997) Regulation of metabolite flux through voltage-gating of VDAC channels. The Journal of membrane biology 157, 271-279. Holtzman, D. M., Bales, K. R., Tenkova, T., Fagan, A. M., Parsadanian, M., Sartorius, L. J., Mackey, B., Olney, J., McKeel, D., Wozniak, D. and Paul, S. M. (2000) Apolipoprotein E isoform-dependent amyloid deposition and neuritic degeneration in a mouse model of Alzheimer's disease. Proceedings of the National Academy of Sciences of the United States of America 97, 2892-2897. Holtzman, D. M., Bales, K. R., Wu, S., Bhat, P., Parsadanian, M., Fagan, A. M., Chang, L. K., Sun, Y. and Paul, S. M. (1999) Expression of human apolipoprotein E reduces amyloid-beta deposition in a mouse model of Alzheimer's disease. The Journal of clinical investigation 103, R15-R21. Hone, E., Martins, I. J., Fonte, J. and Martins, R. N. (2003) Apolipoprotein E influences amyloid-beta clearance from the murine periphery. Journal of Alzheimer's disease : JAD 5, 1-8. Hong, S., Ostaszewski, B. L., Yang, T., O'Malley, T. T., Jin, M., Yanagisawa, K., Li, S., Bartels, T. and Selkoe, D. J. (2014) Soluble Abeta oligomers are rapidly sequestered from brain ISF in vivo and bind GM1 ganglioside on cellular membranes. Neuron 82, 308-319. Hou, L. and Zagorski, M. G. (2006) NMR reveals anomalous copper(II) binding to the amyloid Abeta peptide of Alzheimer's disease. Journal of the American Chemical Society 128, 9260-9261. House, E., Collingwood, J., Khan, A., Korchazkina, O., Berthon, G. and Exley, C. (2004) Aluminium, iron, zinc and copper influence the in vitro formation of amyloid fibrils of Abeta42 in a manner which may have consequences for metal chelation therapy in Alzheimer's disease. Journal of Alzheimer's disease : JAD 6, 291-301. Huang, X., Cuajungco, M. P., Atwood, C. S., Moir, R. D., Tanzi, R. E. and Bush, A. I. (2000) Alzheimer's disease, beta-amyloid protein and zinc. The Journal of nutrition 130, 1488S-1492S. Hughes, S. R., Khorkova, O., Goyal, S., Knaeblein, J., Heroux, J., Riedel, N. G. and Sahasrabudhe, S. (1998) Alpha2-macroglobulin associates with beta-amyloid peptide and prevents fibril formation. Proceedings of the National Academy of Sciences of the United States of America 95, 3275-3280. Hureau, C. and Faller, P. (2009) Abeta-mediated ROS production by Cu ions: structural insights, mechanisms and relevance to Alzheimer's disease. Biochimie 91, 1212-1217. Huttunen, H. J., Fages, C. and Rauvala, H. (1999) Receptor for advanced glycation end products (RAGE)-
Page 50 of 68
Ac ce pt e
d
M
an
us
cr
ip t
mediated neurite outgrowth and activation of NF-kappaB require the cytoplasmic domain of the receptor but different downstream signaling pathways. The Journal of biological chemistry 274, 1991919924. Hye, A., Lynham, S., Thambisetty, M., Causevic, M., Campbell, J., Byers, H. L., Hooper, C., Rijsdijk, F., Tabrizi, S. J., Banner, S., Shaw, C. E., Foy, C., Poppe, M., Archer, N., Hamilton, G., Powell, J., Brown, R. G., Sham, P., Ward, M. and Lovestone, S. (2006) Proteome-based plasma biomarkers for Alzheimer's disease. Brain : a journal of neurology 129, 3042-3050. Isberg, R. R. and Tran Van Nhieu, G. (1994) Binding and internalization of microorganisms by integrin receptors. Trends in microbiology 2, 10-14. Jan, A., Gokce, O., Luthi-Carter, R. and Lashuel, H. A. (2008) The ratio of monomeric to aggregated forms of Abeta40 and Abeta42 is an important determinant of amyloid-beta aggregation, fibrillogenesis, and toxicity. The Journal of biological chemistry 283, 28176-28189. Jana, M., Palencia, C. A. and Pahan, K. (2008) Fibrillar amyloid-beta peptides activate microglia via TLR2: implications for Alzheimer's disease. Journal of immunology 181, 7254-7262. Janciauskiene, S., Garcia de Frutos, P., Carlemalm, E., Dahlback, B. and Eriksson, S. (1995) Inhibition of Alzheimer beta-peptide fibril formation by serum amyloid P component. The Journal of biological chemistry 270, 26041-26044. Janciauskiene, S., Rubin, H., Lukacs, C. M. and Wright, H. T. (1998) Alzheimer's peptide Abeta1-42 binds to two beta-sheets of alpha1-antichymotrypsin and transforms it from inhibitor to substrate. The Journal of biological chemistry 273, 28360-28364. Jiang, Q., Lee, C. Y., Mandrekar, S., Wilkinson, B., Cramer, P., Zelcer, N., Mann, K., Lamb, B., Willson, T. M., Collins, J. L., Richardson, J. C., Smith, J. D., Comery, T. A., Riddell, D., Holtzman, D. M., Tontonoz, P. and Landreth, G. E. (2008) ApoE promotes the proteolytic degradation of Abeta. Neuron 58, 681-693. Joslin, G., Griffin, G. L., August, A. M., Adams, S., Fallon, R. J., Senior, R. M. and Perlmutter, D. H. (1992) The serpin-enzyme complex (SEC) receptor mediates the neutrophil chemotactic effect of alpha-1 antitrypsin-elastase complexes and amyloid-beta peptide. The Journal of clinical investigation 90, 1150-1154. Kakio, A., Nishimoto, S., Yanagisawa, K., Kozutsumi, Y. and Matsuzaki, K. (2002) Interactions of amyloid beta-protein with various gangliosides in raft-like membranes: importance of GM1 ganglioside-bound form as an endogenous seed for Alzheimer amyloid. Biochemistry 41, 7385-7390. Kalaria, R. N. and Perry, G. (1993) Amyloid P component and other acute-phase proteins associated with cerebellar A beta-deposits in Alzheimer's disease. Brain research 631, 151-155. Kallhoff, V., Peethumnongsin, E. and Zheng, H. (2007) Lack of alpha-synuclein increases amyloid plaque accumulation in a transgenic mouse model of Alzheimer's disease. Molecular neurodegeneration 2, 6. Kanekiyo, T., Cirrito, J. R., Liu, C. C., Shinohara, M., Li, J., Schuler, D. R., Shinohara, M., Holtzman, D. M. and Bu, G. (2013) Neuronal clearance of amyloid-beta by endocytic receptor LRP1. The Journal of neuroscience : the official journal of the Society for Neuroscience 33, 19276-19283. Kang, J., Lemaire, H. G., Unterbeck, A., Salbaum, J. M., Masters, C. L., Grzeschik, K. H., Multhaup, G., Beyreuther, K. and Muller-Hill, B. (1987) The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor. Nature 325, 733-736. Kariko, K., Weissman, D. and Welsh, F. A. (2004) Inhibition of toll-like receptor and cytokine signaling--a unifying theme in ischemic tolerance. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 24, 1288-1304. Kawahara, M., Muramoto, K., Kobayashi, K., Mori, H. and Kuroda, Y. (1994) Aluminum promotes the aggregation of Alzheimer's amyloid beta-protein in vitro. Biochemical and biophysical research communications 198, 531-535. Kawamoto, E. M., Lepsch, L. B., Boaventura, M. F., Munhoz, C. D., Lima, L. S., Yshii, L. M., Avellar, M. C., Curi, R., Mattson, M. P. and Scavone, C. (2008) Amyloid beta-peptide activates nuclear factor-kappaB through an N-methyl-D-aspartate signaling pathway in cultured cerebellar cells. Journal of neuroscience research 86, 845-860. Kawarabayashi, T., Younkin, L. H., Saido, T. C., Shoji, M., Ashe, K. H. and Younkin, S. G. (2001) Agedependent changes in brain, CSF, and plasma amyloid (beta) protein in the Tg2576 transgenic mouse model of Alzheimer's disease. The Journal of neuroscience : the official journal of the Society for Neuroscience 21, 372-381. Kessler, H., Bayer, T. A., Bach, D., Schneider-Axmann, T., Supprian, T., Herrmann, W., Haber, M., Multhaup, G., Falkai, P. and Pajonk, F. G. (2008) Intake of copper has no effect on cognition in patients with mild Alzheimer's disease: a pilot phase 2 clinical trial. Journal of neural transmission 115, 1181-1187. Khan, G. M., Tong, M., Jhun, M., Arora, K. and Nichols, R. A. (2010) beta-Amyloid activates presynaptic alpha7 nicotinic acetylcholine receptors reconstituted into a model nerve cell system: involvement of
Page 51 of 68
Ac ce pt e
d
M
an
us
cr
ip t
lipid rafts. The European journal of neuroscience 31, 788-796. Kim, J., Basak, J. M. and Holtzman, D. M. (2009) The role of apolipoprotein E in Alzheimer's disease. Neuron 63, 287-303. Kim, J., Jiang, H., Park, S., Eltorai, A. E., Stewart, F. R., Yoon, H., Basak, J. M., Finn, M. B. and Holtzman, D. M. (2011) Haploinsufficiency of human APOE reduces amyloid deposition in a mouse model of amyloid-beta amyloidosis. The Journal of neuroscience : the official journal of the Society for Neuroscience 31, 18007-18012. Kim, J., Miller, V. M., Levites, Y., West, K. J., Zwizinski, C. W., Moore, B. D., Troendle, F. J., Bann, M., Verbeeck, C., Price, R. W., Smithson, L., Sonoda, L., Wagg, K., Rangachari, V., Zou, F., Younkin, S. G., Graff-Radford, N., Dickson, D., Rosenberry, T. and Golde, T. E. (2008) BRI2 (ITM2b) inhibits Abeta deposition in vivo. The Journal of neuroscience : the official journal of the Society for Neuroscience 28, 6030-6036. Kim, J., Onstead, L., Randle, S., Price, R., Smithson, L., Zwizinski, C., Dickson, D. W., Golde, T. and McGowan, E. (2007) Abeta40 inhibits amyloid deposition in vivo. The Journal of neuroscience : the official journal of the Society for Neuroscience 27, 627-633. Kim, T., Vidal, G. S., Djurisic, M., William, C. M., Birnbaum, M. E., Garcia, K. C., Hyman, B. T. and Shatz, C. J. (2013) Human LilrB2 is a beta-amyloid receptor and its murine homolog PirB regulates synaptic plasticity in an Alzheimer's model. Science 341, 1399-1404. Kim, T. S., Pae, C. U., Yoon, S. J., Jang, W. Y., Lee, N. J., Kim, J. J., Lee, S. J., Lee, C., Paik, I. H. and Lee, C. U. (2006) Decreased plasma antioxidants in patients with Alzheimer's disease. International journal of geriatric psychiatry 21, 344-348. Kitazawa, M., Cheng, D. and Laferla, F. M. (2009) Chronic copper exposure exacerbates both amyloid and tau pathology and selectively dysregulates cdk5 in a mouse model of AD. Journal of neurochemistry 108, 1550-1560. Klann, E. (2002) Metaplastic protein phosphatases. Learning & memory 9, 153-155. Koenigsknecht, J. and Landreth, G. (2004) Microglial phagocytosis of fibrillar beta-amyloid through a beta1 integrin-dependent mechanism. The Journal of neuroscience : the official journal of the Society for Neuroscience 24, 9838-9846. Kook, S. Y., Hong, H. S., Moon, M., Ha, C. M., Chang, S. and Mook-Jung, I. (2012) Abeta(1)(-)(4)(2)-RAGE interaction disrupts tight junctions of the blood-brain barrier via Ca(2)(+)-calcineurin signaling. The Journal of neuroscience : the official journal of the Society for Neuroscience 32, 8845-8854. Korchazhkina, O. V., Ashcroft, A. E., Kiss, T. and Exley, C. (2002) The degradation of Abeta(25-35) by the serine protease plasmin is inhibited by aluminium. Journal of Alzheimer's disease : JAD 4, 357-367. Kovacs, D. M. (2000) alpha2-macroglobulin in late-onset Alzheimer's disease. Experimental gerontology 35, 473-479. Kozin, S. A., Zirah, S., Rebuffat, S., Hoa, G. H. and Debey, P. (2001) Zinc binding to Alzheimer's Abeta(1-16) peptide results in stable soluble complex. Biochemical and biophysical research communications 285, 959-964. Kudo, W., Lee, H. P., Zou, W. Q., Wang, X., Perry, G., Zhu, X., Smith, M. A., Petersen, R. B. and Lee, H. G. (2012) Cellular prion protein is essential for oligomeric amyloid-beta-induced neuronal cell death. Human molecular genetics 21, 1138-1144. Kuo, Y. M., Kokjohn, T. A., Kalback, W., Luehrs, D., Galasko, D. R., Chevallier, N., Koo, E. H., Emmerling, M. R. and Roher, A. E. (2000) Amyloid-beta peptides interact with plasma proteins and erythrocytes: implications for their quantitation in plasma. Biochemical and biophysical research communications 268, 750-756. Kurochkin, I. V. (1998) Amyloidogenic determinant as a substrate recognition motif of insulin-degrading enzyme. FEBS letters 427, 153-156. Kuszczyk, M. A., Sanchez, S., Pankiewicz, J., Kim, J., Duszczyk, M., Guridi, M., Asuni, A. A., Sullivan, P. M., Holtzman, D. M. and Sadowski, M. J. (2013) Blocking the interaction between apolipoprotein E and Abeta reduces intraneuronal accumulation of Abeta and inhibits synaptic degeneration. The American journal of pathology 182, 1750-1768. Lacor, P. N., Buniel, M. C., Furlow, P. W., Clemente, A. S., Velasco, P. T., Wood, M., Viola, K. L. and Klein, W. L. (2007) Abeta oligomer-induced aberrations in synapse composition, shape, and density provide a molecular basis for loss of connectivity in Alzheimer's disease. The Journal of neuroscience : the official journal of the Society for Neuroscience 27, 796-807. LaDu, M. J., Falduto, M. T., Manelli, A. M., Reardon, C. A., Getz, G. S. and Frail, D. E. (1994) Isoform-specific binding of apolipoprotein E to beta-amyloid. The Journal of biological chemistry 269, 23403-23406. LaFerla, F. M., Green, K. N. and Oddo, S. (2007) Intracellular amyloid-beta in Alzheimer's disease. Nature reviews. Neuroscience 8, 499-509.
Page 52 of 68
Ac ce pt e
d
M
an
us
cr
ip t
Lannfelt, L., Blennow, K., Zetterberg, H., Batsman, S., Ames, D., Harrison, J., Masters, C. L., Targum, S., Bush, A. I., Murdoch, R., Wilson, J., Ritchie, C. W. and group, P. E. s. (2008) Safety, efficacy, and biomarker findings of PBT2 in targeting Abeta as a modifying therapy for Alzheimer's disease: a phase IIa, double-blind, randomised, placebo-controlled trial. Lancet neurology 7, 779-786. Lauer, D., Reichenbach, A. and Birkenmeier, G. (2001) Alpha 2-macroglobulin-mediated degradation of amyloid beta 1--42: a mechanism to enhance amyloid beta catabolism. Experimental neurology 167, 385-392. Lauren, J., Gimbel, D. A., Nygaard, H. B., Gilbert, J. W. and Strittmatter, S. M. (2009) Cellular prion protein mediates impairment of synaptic plasticity by amyloid-beta oligomers. Nature 457, 1128-1132. Le, Y., Gong, W., Tiffany, H. L., Tumanov, A., Nedospasov, S., Shen, W., Dunlop, N. M., Gao, J. L., Murphy, P. M., Oppenheim, J. J. and Wang, J. M. (2001) Amyloid (beta)42 activates a G-protein-coupled chemoattractant receptor, FPR-like-1. The Journal of neuroscience : the official journal of the Society for Neuroscience 21, RC123. Lee, D. H. and Wang, H. Y. (2003) Differential physiologic responses of alpha7 nicotinic acetylcholine receptors to beta-amyloid1-40 and beta-amyloid1-42. Journal of neurobiology 55, 25-30. Lei, P., Ayton, S., Finkelstein, D. I., Spoerri, L., Ciccotosto, G. D., Wright, D. K., Wong, B. X., Adlard, P. A., Cherny, R. A., Lam, L. Q., Roberts, B. R., Volitakis, I., Egan, G. F., McLean, C. A., Cappai, R., Duce, J. A. and Bush, A. I. (2012) Tau deficiency induces parkinsonism with dementia by impairing APPmediated iron export. Nature medicine 18, 291-295. Letiembre, M., Liu, Y., Walter, S., Hao, W., Pfander, T., Wrede, A., Schulz-Schaeffer, W. and Fassbender, K. (2009) Screening of innate immune receptors in neurodegenerative diseases: a similar pattern. Neurobiology of aging 30, 759-768. Ling, X., Martins, R. N., Racchi, M., Craft, S. and Helmerhorst, E. (2002) Amyloid beta antagonizes insulin promoted secretion of the amyloid beta protein precursor. Journal of Alzheimer's disease : JAD 4, 369374. Liu, Q., Kawai, H. and Berg, D. K. (2001) beta -Amyloid peptide blocks the response of alpha 7-containing nicotinic receptors on hippocampal neurons. Proceedings of the National Academy of Sciences of the United States of America 98, 4734-4739. Liu, Q., Trotter, J., Zhang, J., Peters, M. M., Cheng, H., Bao, J., Han, X., Weeber, E. J. and Bu, G. (2010) Neuronal LRP1 knockout in adult mice leads to impaired brain lipid metabolism and progressive, agedependent synapse loss and neurodegeneration. The Journal of neuroscience : the official journal of the Society for Neuroscience 30, 17068-17078. Liu, S., Liu, Y., Hao, W., Wolf, L., Kiliaan, A. J., Penke, B., Rube, C. E., Walter, J., Heneka, M. T., Hartmann, T., Menger, M. D. and Fassbender, K. (2012) TLR2 is a primary receptor for Alzheimer's amyloid beta peptide to trigger neuroinflammatory activation. Journal of immunology 188, 1098-1107. Llewellyn, D. J., Langa, K. M., Friedland, R. P. and Lang, I. A. (2010) Serum albumin concentration and cognitive impairment. Current Alzheimer research 7, 91-96. Lorenzo, A., Yuan, M., Zhang, Z., Paganetti, P. A., Sturchler-Pierrat, C., Staufenbiel, M., Mautino, J., Vigo, F. S., Sommer, B. and Yankner, B. A. (2000) Amyloid beta interacts with the amyloid precursor protein: a potential toxic mechanism in Alzheimer's disease. Nature neuroscience 3, 460-464. Lovell, M. A., Robertson, J. D., Teesdale, W. J., Campbell, J. L. and Markesbery, W. R. (1998) Copper, iron and zinc in Alzheimer's disease senile plaques. Journal of the neurological sciences 158, 47-52. Lue, L. F., Walker, D. G., Brachova, L., Beach, T. G., Rogers, J., Schmidt, A. M., Stern, D. M. and Yan, S. D. (2001) Involvement of microglial receptor for advanced glycation endproducts (RAGE) in Alzheimer's disease: identification of a cellular activation mechanism. Experimental neurology 171, 29-45. Lustbader, J. W., Cirilli, M., Lin, C., Xu, H. W., Takuma, K., Wang, N., Caspersen, C., Chen, X., Pollak, S., Chaney, M., Trinchese, F., Liu, S., Gunn-Moore, F., Lue, L. F., Walker, D. G., Kuppusamy, P., Zewier, Z. L., Arancio, O., Stern, D., Yan, S. S. and Wu, H. (2004) ABAD directly links Abeta to mitochondrial toxicity in Alzheimer's disease. Science 304, 448-452. Ma, J., Yee, A., Brewer, H. B., Jr., Das, S. and Potter, H. (1994) Amyloid-associated proteins alpha 1antichymotrypsin and apolipoprotein E promote assembly of Alzheimer beta-protein into filaments. Nature 372, 92-94. Ma, Q. F., Li, Y. M., Du, J. T., Kanazawa, K., Nemoto, T., Nakanishi, H. and Zhao, Y. F. (2005) Binding of copper (II) ion to an Alzheimer's tau peptide as revealed by MALDI-TOF MS, CD, and NMR. Biopolymers 79, 74-85. Mackic, J. B., Stins, M., McComb, J. G., Calero, M., Ghiso, J., Kim, K. S., Yan, S. D., Stern, D., Schmidt, A. M., Frangione, B. and Zlokovic, B. V. (1998) Human blood-brain barrier receptors for Alzheimer's amyloid-beta 1- 40. Asymmetrical binding, endocytosis, and transcytosis at the apical side of brain microvascular endothelial cell monolayer. The Journal of clinical investigation 102, 734-743.
Page 53 of 68
Ac ce pt e
d
M
an
us
cr
ip t
Maes, M., DeVos, N., Wauters, A., Demedts, P., Maurits, V. W., Neels, H., Bosmans, E., Altamura, C., Lin, A., Song, C., Vandenbroucke, M. and Scharpe, S. (1999) Inflammatory markers in younger vs elderly normal volunteers and in patients with Alzheimer's disease. Journal of psychiatric research 33, 397405. Manczak, M., Calkins, M. J. and Reddy, P. H. (2011) Impaired mitochondrial dynamics and abnormal interaction of amyloid beta with mitochondrial protein Drp1 in neurons from patients with Alzheimer's disease: implications for neuronal damage. Human molecular genetics 20, 2495-2509. Manczak, M. and Reddy, P. H. (2012a) Abnormal interaction between the mitochondrial fission protein Drp1 and hyperphosphorylated tau in Alzheimer's disease neurons: implications for mitochondrial dysfunction and neuronal damage. Human molecular genetics 21, 2538-2547. Manczak, M. and Reddy, P. H. (2012b) Abnormal interaction of VDAC1 with amyloid beta and phosphorylated tau causes mitochondrial dysfunction in Alzheimer's disease. Human molecular genetics 21, 5131-5146. Mandal, P. K., Pettegrew, J. W., Masliah, E., Hamilton, R. L. and Mandal, R. (2006) Interaction between Abeta peptide and alpha synuclein: molecular mechanisms in overlapping pathology of Alzheimer's and Parkinson's in dementia with Lewy body disease. Neurochemical research 31, 1153-1162. Mantyh, P. W., Ghilardi, J. R., Rogers, S., DeMaster, E., Allen, C. J., Stimson, E. R. and Maggio, J. E. (1993) Aluminum, iron, and zinc ions promote aggregation of physiological concentrations of beta-amyloid peptide. Journal of neurochemistry 61, 1171-1174. Marques, M. A., Kulstad, J. J., Savard, C. E., Green, P. S., Lee, S. P., Craft, S., Watson, G. S. and Cook, D. G. (2009) Peripheral amyloid-beta levels regulate amyloid-beta clearance from the central nervous system. Journal of Alzheimer's disease : JAD 16, 325-329. Martic, S., Rains, M. K. and Kraatz, H. B. (2013) Probing copper/tau protein interactions electrochemically. Analytical biochemistry 442, 130-137. Masliah, E., Rockenstein, E., Veinbergs, I., Sagara, Y., Mallory, M., Hashimoto, M. and Mucke, L. (2001) betaamyloid peptides enhance alpha-synuclein accumulation and neuronal deficits in a transgenic mouse model linking Alzheimer's disease and Parkinson's disease. Proceedings of the National Academy of Sciences of the United States of America 98, 12245-12250. Matsubara, E., Frangione, B. and Ghiso, J. (1995) Characterization of apolipoprotein J-Alzheimer's A beta interaction. The Journal of biological chemistry 270, 7563-7567. Matsuoka, Y., Saito, M., LaFrancois, J., Saito, M., Gaynor, K., Olm, V., Wang, L., Casey, E., Lu, Y., Shiratori, C., Lemere, C. and Duff, K. (2003) Novel therapeutic approach for the treatment of Alzheimer's disease by peripheral administration of agents with an affinity to beta-amyloid. The Journal of neuroscience : the official journal of the Society for Neuroscience 23, 29-33. Matter, M. L., Zhang, Z., Nordstedt, C. and Ruoslahti, E. (1998) The alpha5beta1 integrin mediates elimination of amyloid-beta peptide and protects against apoptosis. The Journal of cell biology 141, 1019-1030. Mawuenyega, K. G., Sigurdson, W., Ovod, V., Munsell, L., Kasten, T., Morris, J. C., Yarasheski, K. E. and Bateman, R. J. (2010) Decreased clearance of CNS beta-amyloid in Alzheimer's disease. Science 330, 1774. May, P. C., Lampert-Etchells, M., Johnson, S. A., Poirier, J., Masters, J. N. and Finch, C. E. (1990) Dynamics of gene expression for a hippocampal glycoprotein elevated in Alzheimer's disease and in response to experimental lesions in rat. Neuron 5, 831-839. McDonald, D. R., Brunden, K. R. and Landreth, G. E. (1997) Amyloid fibrils activate tyrosine kinase-dependent signaling and superoxide production in microglia. The Journal of neuroscience : the official journal of the Society for Neuroscience 17, 2284-2294. McGeer, P. L., Kawamata, T. and Walker, D. G. (1992) Distribution of clusterin in Alzheimer brain tissue. Brain research 579, 337-341. Medzhitov, R. (2001) Toll-like receptors and innate immunity. Nature reviews. Immunology 1, 135-145. Mehta, T. K., Dougherty, J. J., Wu, J., Choi, C. H., Khan, G. M. and Nichols, R. A. (2009) Defining pre-synaptic nicotinic receptors regulated by beta amyloid in mouse cortex and hippocampus with receptor null mutants. Journal of neurochemistry 109, 1452-1458. Michaud, J. P., Halle, M., Lampron, A., Theriault, P., Prefontaine, P., Filali, M., Tribout-Jover, P., Lanteigne, A. M., Jodoin, R., Cluff, C., Brichard, V., Palmantier, R., Pilorget, A., Larocque, D. and Rivest, S. (2013) Toll-like receptor 4 stimulation with the detoxified ligand monophosphoryl lipid A improves Alzheimer's disease-related pathology. Proceedings of the National Academy of Sciences of the United States of America 110, 1941-1946. Mick, D. U., Fox, T. D. and Rehling, P. (2011) Inventory control: cytochrome c oxidase assembly regulates mitochondrial translation. Nature reviews. Molecular cell biology 12, 14-20. Milward, E. A., Papadopoulos, R., Fuller, S. J., Moir, R. D., Small, D., Beyreuther, K. and Masters, C. L. (1992) The amyloid protein precursor of Alzheimer's disease is a mediator of the effects of nerve growth factor
Page 54 of 68
Ac ce pt e
d
M
an
us
cr
ip t
on neurite outgrowth. Neuron 9, 129-137. Mizuno, T. (2012) The biphasic role of microglia in Alzheimer's disease. International journal of Alzheimer's disease 2012, 737846. Mold, M., Shrive, A. K. and Exley, C. (2012) Serum amyloid P component accelerates the formation and enhances the stability of amyloid fibrils in a physiologically significant under-saturated solution of amyloid-beta42. Journal of Alzheimer's disease : JAD 29, 875-881. Moreira, P. I., Santos, M. S., Moreno, A., Rego, A. C. and Oliveira, C. (2002) Effect of amyloid beta-peptide on permeability transition pore: a comparative study. Journal of neuroscience research 69, 257-267. Morgan, D., Gordon, M. N., Tan, J., Wilcock, D. and Rojiani, A. M. (2005) Dynamic complexity of the microglial activation response in transgenic models of amyloid deposition: implications for Alzheimer therapeutics. Journal of neuropathology and experimental neurology 64, 743-753. Murray, M. M., Bernstein, S. L., Nyugen, V., Condron, M. M., Teplow, D. B. and Bowers, M. T. (2009) Amyloid beta protein: Abeta40 inhibits Abeta42 oligomerization. Journal of the American Chemical Society 131, 6316-6317. Neri, L. C. and Hewitt, D. (1991) Aluminium, Alzheimer's disease, and drinking water. Lancet 338, 390. Nicoll, A. J., Panico, S., Freir, D. B., Wright, D., Terry, C., Risse, E., Herron, C. E., O'Malley, T., Wadsworth, J. D., Farrow, M. A., Walsh, D. M., Saibil, H. R. and Collinge, J. (2013) Amyloid-beta nanotubes are associated with prion protein-dependent synaptotoxicity. Nature communications 4, 2416. Nilsson, L. N., Bales, K. R., DiCarlo, G., Gordon, M. N., Morgan, D., Paul, S. M. and Potter, H. (2001) Alpha1-antichymotrypsin promotes beta-sheet amyloid plaque deposition in a transgenic mouse model of Alzheimer's disease. The Journal of neuroscience : the official journal of the Society for Neuroscience 21, 1444-1451. Oda, T., Pasinetti, G. M., Osterburg, H. H., Anderson, C., Johnson, S. A. and Finch, C. E. (1994) Purification and characterization of brain clusterin. Biochemical and biophysical research communications 204, 1131-1136. Ono, K., Noguchi-Shinohara, M., Yoshita, M., Naiki, H. and Yamada, M. (2007) Cerebrospinal fluid of Alzheimer's disease and dementia with Lewy bodies patients enhances alpha-synuclein fibril formation in vitro. Experimental neurology 203, 579-583. Ono, K., Takahashi, R., Ikeda, T. and Yamada, M. (2012) Cross-seeding effects of amyloid beta-protein and alpha-synuclein. Journal of neurochemistry 122, 883-890. Origlia, N., Bonadonna, C., Rosellini, A., Leznik, E., Arancio, O., Yan, S. S. and Domenici, L. (2010) Microglial receptor for advanced glycation end product-dependent signal pathway drives beta-amyloid-induced synaptic depression and long-term depression impairment in entorhinal cortex. The Journal of neuroscience : the official journal of the Society for Neuroscience 30, 11414-11425. Origlia, N., Righi, M., Capsoni, S., Cattaneo, A., Fang, F., Stern, D. M., Chen, J. X., Schmidt, A. M., Arancio, O., Yan, S. D. and Domenici, L. (2008) Receptor for advanced glycation end product-dependent activation of p38 mitogen-activated protein kinase contributes to amyloid-beta-mediated cortical synaptic dysfunction. The Journal of neuroscience : the official journal of the Society for Neuroscience 28, 3521-3530. Palop, J. J. and Mucke, L. (2010) Amyloid-beta-induced neuronal dysfunction in Alzheimer's disease: from synapses toward neural networks. Nature neuroscience 13, 812-818. Panegyres, P. K. (2001) The functions of the amyloid precursor protein gene. Reviews in the neurosciences 12, 1-39. Pankiewicz, J. E., Guridi, M., Kim, J., Asuni, A. A., Sanchez, S., Sullivan, P. M., Holtzman, D. M. and Sadowski, M. J. (2014) Blocking the apoE/Abeta interaction ameliorates Abeta-related pathology in APOE epsilon2 and epsilon4 targeted replacement Alzheimer model mice. Acta neuropathologica communications 2, 75. Paresce, D. M., Ghosh, R. N. and Maxfield, F. R. (1996) Microglial cells internalize aggregates of the Alzheimer's disease amyloid beta-protein via a scavenger receptor. Neuron 17, 553-565. Park, L., Wang, G., Zhou, P., Zhou, J., Pitstick, R., Previti, M. L., Younkin, L., Younkin, S. G., Van Nostrand, W. E., Cho, S., Anrather, J., Carlson, G. A. and Iadecola, C. (2011) Scavenger receptor CD36 is essential for the cerebrovascular oxidative stress and neurovascular dysfunction induced by amyloid-beta. Proceedings of the National Academy of Sciences of the United States of America 108, 5063-5068. Park, L., Zhou, J., Zhou, P., Pistick, R., El Jamal, S., Younkin, L., Pierce, J., Arreguin, A., Anrather, J., Younkin, S. G., Carlson, G. A., McEwen, B. S. and Iadecola, C. (2013) Innate immunity receptor CD36 promotes cerebral amyloid angiopathy. Proceedings of the National Academy of Sciences of the United States of America 110, 3089-3094. Parks, J. K., Smith, T. S., Trimmer, P. A., Bennett, J. P., Jr. and Parker, W. D., Jr. (2001) Neurotoxic Abeta peptides increase oxidative stress in vivo through NMDA-receptor and nitric-oxide-synthase
Page 55 of 68
Ac ce pt e
d
M
an
us
cr
ip t
mechanisms, and inhibit complex IV activity and induce a mitochondrial permeability transition in vitro. Journal of neurochemistry 76, 1050-1056. Pettit, D. L., Shao, Z. and Yakel, J. L. (2001) beta-Amyloid(1-42) peptide directly modulates nicotinic receptors in the rat hippocampal slice. The Journal of neuroscience : the official journal of the Society for Neuroscience 21, RC120. Pickrell, A. M., Fukui, H. and Moraes, C. T. (2009) The role of cytochrome c oxidase deficiency in ROS and amyloid plaque formation. Journal of bioenergetics and biomembranes 41, 453-456. Pinho, C. M., Teixeira, P. F. and Glaser, E. (2014) Mitochondrial import and degradation of amyloid-beta peptide. Biochimica et biophysica acta. Poelmans, G., Buitelaar, J. K., Pauls, D. L. and Franke, B. (2011) A theoretical molecular network for dyslexia: integrating available genetic findings. Molecular psychiatry 16, 365-382. Puchades, M., Hansson, S. F., Nilsson, C. L., Andreasen, N., Blennow, K. and Davidsson, P. (2003) Proteomic studies of potential cerebrospinal fluid protein markers for Alzheimer's disease. Brain research. Molecular brain research 118, 140-146. Qiu, Z., Strickland, D. K., Hyman, B. T. and Rebeck, G. W. (1999) Alpha2-macroglobulin enhances the clearance of endogenous soluble beta-amyloid peptide via low-density lipoprotein receptor-related protein in cortical neurons. Journal of neurochemistry 73, 1393-1398. Querfurth, H. W. and LaFerla, F. M. (2010) Alzheimer's disease. The New England journal of medicine 362, 329-344. Raman, B., Ban, T., Yamaguchi, K., Sakai, M., Kawai, T., Naiki, H. and Goto, Y. (2005) Metal ion-dependent effects of clioquinol on the fibril growth of an amyloid {beta} peptide. The Journal of biological chemistry 280, 16157-16162. Reed-Geaghan, E. G., Savage, J. C., Hise, A. G. and Landreth, G. E. (2009) CD14 and toll-like receptors 2 and 4 are required for fibrillar A{beta}-stimulated microglial activation. The Journal of neuroscience : the official journal of the Society for Neuroscience 29, 11982-11992. Religa, D., Strozyk, D., Cherny, R. A., Volitakis, I., Haroutunian, V., Winblad, B., Naslund, J. and Bush, A. I. (2006) Elevated cortical zinc in Alzheimer disease. Neurology 67, 69-75. Renkawek, K., Voorter, C. E., Bosman, G. J., van Workum, F. P. and de Jong, W. W. (1994) Expression of alpha B-crystallin in Alzheimer's disease. Acta neuropathologica 87, 155-160. Rezaei-Ghaleh, N., Giller, K., Becker, S. and Zweckstetter, M. (2011) Effect of zinc binding on beta-amyloid structure and dynamics: implications for Abeta aggregation. Biophysical journal 101, 1202-1211. Richard, K. L., Filali, M., Prefontaine, P. and Rivest, S. (2008) Toll-like receptor 2 acts as a natural innate immune receptor to clear amyloid beta 1-42 and delay the cognitive decline in a mouse model of Alzheimer's disease. The Journal of neuroscience : the official journal of the Society for Neuroscience 28, 5784-5793. Riehl, A., Nemeth, J., Angel, P. and Hess, J. (2009) The receptor RAGE: Bridging inflammation and cancer. Cell communication and signaling : CCS 7, 12. Rottkamp, C. A., Raina, A. K., Zhu, X., Gaier, E., Bush, A. I., Atwood, C. S., Chevion, M., Perry, G. and Smith, M. A. (2001) Redox-active iron mediates amyloid-beta toxicity. Free radical biology & medicine 30, 447-450. Rulon, L. L., Robertson, J. D., Lovell, M. A., Deibel, M. A., Ehmann, W. D. and Markesber, W. R. (2000) Serum zinc levels and Alzheimer's disease. Biological trace element research 75, 79-85. Rushworth, J. V., Griffiths, H. H., Watt, N. T. and Hooper, N. M. (2013) Prion protein-mediated toxicity of amyloid-beta oligomers requires lipid rafts and the transmembrane LRP1. The Journal of biological chemistry 288, 8935-8951. Sabbagh, M. N., Agro, A., Bell, J., Aisen, P. S., Schweizer, E. and Galasko, D. (2011) PF-04494700, an oral inhibitor of receptor for advanced glycation end products (RAGE), in Alzheimer disease. Alzheimer disease and associated disorders 25, 206-212. Sabo, S., Lambert, M. P., Kessey, K., Wade, W., Krafft, G. and Klein, W. L. (1995) Interaction of beta-amyloid peptides with integrins in a human nerve cell line. Neuroscience letters 184, 25-28. Saito, Y., Akiyama, M., Araki, Y., Sumioka, A., Shiono, M., Taru, H., Nakaya, T., Yamamoto, T. and Suzuki, T. (2011) Intracellular trafficking of the amyloid beta-protein precursor (APP) regulated by novel function of X11-like. PloS one 6, e22108. Sanan, D. A., Weisgraber, K. H., Russell, S. J., Mahley, R. W., Huang, D., Saunders, A., Schmechel, D., Wisniewski, T., Frangione, B., Roses, A. D. and et al. (1994) Apolipoprotein E associates with beta amyloid peptide of Alzheimer's disease to form novel monofibrils. Isoform apoE4 associates more efficiently than apoE3. The Journal of clinical investigation 94, 860-869. Santos, R. X., Correia, S. C., Wang, X., Perry, G., Smith, M. A., Moreira, P. I. and Zhu, X. (2010) A synergistic dysfunction of mitochondrial fission/fusion dynamics and mitophagy in Alzheimer's disease. Journal of
Page 56 of 68
Ac ce pt e
d
M
an
us
cr
ip t
Alzheimer's disease : JAD 20 Suppl 2, S401-412. Sayre, L. M., Perry, G., Harris, P. L., Liu, Y., Schubert, K. A. and Smith, M. A. (2000) In situ oxidative catalysis by neurofibrillary tangles and senile plaques in Alzheimer's disease: a central role for bound transition metals. Journal of neurochemistry 74, 270-279. Schinzel, A. C., Takeuchi, O., Huang, Z., Fisher, J. K., Zhou, Z., Rubens, J., Hetz, C., Danial, N. N., Moskowitz, M. A. and Korsmeyer, S. J. (2005) Cyclophilin D is a component of mitochondrial permeability transition and mediates neuronal cell death after focal cerebral ischemia. Proceedings of the National Academy of Sciences of the United States of America 102, 12005-12010. Schmidt, C., Lepsverdize, E., Chi, S. L., Das, A. M., Pizzo, S. V., Dityatev, A. and Schachner, M. (2008) Amyloid precursor protein and amyloid beta-peptide bind to ATP synthase and regulate its activity at the surface of neural cells. Molecular psychiatry 13, 953-969. Schwarzman, A. L. and Goldgaber, D. (1996) Interaction of transthyretin with amyloid beta-protein: binding and inhibition of amyloid formation. Ciba Foundation symposium 199, 146-160; discussion 160-144. Schwarzman, A. L., Gregori, L., Vitek, M. P., Lyubski, S., Strittmatter, W. J., Enghilde, J. J., Bhasin, R., Silverman, J., Weisgraber, K. H., Coyle, P. K. and et al. (1994) Transthyretin sequesters amyloid beta protein and prevents amyloid formation. Proceedings of the National Academy of Sciences of the United States of America 91, 8368-8372. Seo, J. S., Lee, K. W., Kim, T. K., Baek, I. S., Im, J. Y. and Han, P. L. (2011) Behavioral stress causes mitochondrial dysfunction via ABAD up-regulation and aggravates plaque pathology in the brain of a mouse model of Alzheimer disease. Free radical biology & medicine 50, 1526-1535. Sharma, A. K., Pavlova, S. T., Kim, J., Finkelstein, D., Hawco, N. J., Rath, N. P., Kim, J. and Mirica, L. M. (2012) Bifunctional compounds for controlling metal-mediated aggregation of the abeta42 peptide. Journal of the American Chemical Society 134, 6625-6636. Shibata, M., Yamada, S., Kumar, S. R., Calero, M., Bading, J., Frangione, B., Holtzman, D. M., Miller, C. A., Strickland, D. K., Ghiso, J. and Zlokovic, B. V. (2000) Clearance of Alzheimer's amyloid-ss(1-40) peptide from brain by LDL receptor-related protein-1 at the blood-brain barrier. The Journal of clinical investigation 106, 1489-1499. Simon, A. M., de Maturana, R. L., Ricobaraza, A., Escribano, L., Schiapparelli, L., Cuadrado-Tejedor, M., Perez-Mediavilla, A., Avila, J., Del Rio, J. and Frechilla, D. (2009) Early changes in hippocampal Eph receptors precede the onset of memory decline in mouse models of Alzheimer's disease. Journal of Alzheimer's disease : JAD 17, 773-786. Singh, I., Sagare, A. P., Coma, M., Perlmutter, D., Gelein, R., Bell, R. D., Deane, R. J., Zhong, E., Parisi, M., Ciszewski, J., Kasper, R. T. and Deane, R. (2013) Low levels of copper disrupt brain amyloid-beta homeostasis by altering its production and clearance. Proceedings of the National Academy of Sciences of the United States of America 110, 14771-14776. Small, D. H., Maksel, D., Kerr, M. L., Ng, J., Hou, X., Chu, C., Mehrani, H., Unabia, S., Azari, M. F., Loiacono, R., Aguilar, M. I. and Chebib, M. (2007) The beta-amyloid protein of Alzheimer's disease binds to membrane lipids but does not bind to the alpha7 nicotinic acetylcholine receptor. Journal of neurochemistry 101, 1527-1538. Smilansky, A., Dangoor, L., Nakdimon, I., Ben-Hail, D., Mizrachi, D. and Shoshan-Barmatz, V. (2015) The voltage-dependent anion channel 1 mediates amyloid beta toxicity and represents a potential target for Alzheimer's disease therapy. The Journal of biological chemistry. Smith, M. A., Harris, P. L., Sayre, L. M. and Perry, G. (1997) Iron accumulation in Alzheimer disease is a source of redox-generated free radicals. Proceedings of the National Academy of Sciences of the United States of America 94, 9866-9868. Sousa, J. C., Cardoso, I., Marques, F., Saraiva, M. J. and Palha, J. A. (2007) Transthyretin and Alzheimer's disease: where in the brain? Neurobiology of aging 28, 713-718. Squitti, R., Lupoi, D., Pasqualetti, P., Dal Forno, G., Vernieri, F., Chiovenda, P., Rossi, L., Cortesi, M., Cassetta, E. and Rossini, P. M. (2002) Elevation of serum copper levels in Alzheimer's disease. Neurology 59, 1153-1161. Stanyon, H. F. and Viles, J. H. (2012) Human serum albumin can regulate amyloid-beta peptide fiber growth in the brain interstitium: implications for Alzheimer disease. The Journal of biological chemistry 287, 28163-28168. Stein, T. D. and Johnson, J. A. (2002) Lack of neurodegeneration in transgenic mice overexpressing mutant amyloid precursor protein is associated with increased levels of transthyretin and the activation of cell survival pathways. The Journal of neuroscience : the official journal of the Society for Neuroscience 22, 7380-7388. Stevens, R. W., Elmendorf, D., Gourlay, M., Stroebel, E. and Gaafar, H. A. (1979) Application of fluoroimmunoassay to cerebrospinal fluid immunoglobulin G and albumin. Journal of clinical
Page 57 of 68
Ac ce pt e
d
M
an
us
cr
ip t
microbiology 10, 346-350. Strittmatter, W. J., Saunders, A. M., Schmechel, D., Pericak-Vance, M., Enghild, J., Salvesen, G. S. and Roses, A. D. (1993a) Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proceedings of the National Academy of Sciences of the United States of America 90, 1977-1981. Strittmatter, W. J., Weisgraber, K. H., Huang, D. Y., Dong, L. M., Salvesen, G. S., Pericak-Vance, M., Schmechel, D., Saunders, A. M., Goldgaber, D. and Roses, A. D. (1993b) Binding of human apolipoprotein E to synthetic amyloid beta peptide: isoform-specific effects and implications for lateonset Alzheimer disease. Proceedings of the National Academy of Sciences of the United States of America 90, 8098-8102. Strober, W., Murray, P. J., Kitani, A. and Watanabe, T. (2006) Signalling pathways and molecular interactions of NOD1 and NOD2. Nature reviews. Immunology 6, 9-20. Sturchler, E., Galichet, A., Weibel, M., Leclerc, E. and Heizmann, C. W. (2008) Site-specific blockade of RAGE-Vd prevents amyloid-beta oligomer neurotoxicity. The Journal of neuroscience : the official journal of the Society for Neuroscience 28, 5149-5158. Suen, D. F., Norris, K. L. and Youle, R. J. (2008) Mitochondrial dynamics and apoptosis. Genes & development 22, 1577-1590. Suh, S. W., Jensen, K. B., Jensen, M. S., Silva, D. S., Kesslak, P. J., Danscher, G. and Frederickson, C. J. (2000) Histochemically-reactive zinc in amyloid plaques, angiopathy, and degenerating neurons of Alzheimer's diseased brains. Brain research 852, 274-278. Sun, X. Y., Wei, Y. P., Xiong, Y., Wang, X. C., Xie, A. J., Wang, X. L., Yang, Y., Wang, Q., Lu, Y. M., Liu, R. and Wang, J. Z. (2012) Synaptic released zinc promotes tau hyperphosphorylation by inhibition of protein phosphatase 2A (PP2A). The Journal of biological chemistry 287, 11174-11182. Sutcliffe, J. G., Hedlund, P. B., Thomas, E. A., Bloom, F. E. and Hilbush, B. S. (2011) Peripheral reduction of beta-amyloid is sufficient to reduce brain beta-amyloid: implications for Alzheimer's disease. Journal of neuroscience research 89, 808-814. Suzuki, K., Miura, T. and Takeuchi, H. (2001) Inhibitory effect of copper(II) on zinc(II)-induced aggregation of amyloid beta-peptide. Biochemical and biophysical research communications 285, 991-996. Syken, J., Grandpre, T., Kanold, P. O. and Shatz, C. J. (2006) PirB restricts ocular-dominance plasticity in visual cortex. Science 313, 1795-1800. Taguchi, A., Blood, D. C., del Toro, G., Canet, A., Lee, D. C., Qu, W., Tanji, N., Lu, Y., Lalla, E., Fu, C., Hofmann, M. A., Kislinger, T., Ingram, M., Lu, A., Tanaka, H., Hori, O., Ogawa, S., Stern, D. M. and Schmidt, A. M. (2000) Blockade of RAGE-amphoterin signalling suppresses tumour growth and metastases. Nature 405, 354-360. Tahara, K., Kim, H. D., Jin, J. J., Maxwell, J. A., Li, L. and Fukuchi, K. (2006) Role of toll-like receptor signalling in Abeta uptake and clearance. Brain : a journal of neurology 129, 3006-3019. Takai, T. (2005) Paired immunoglobulin-like receptors and their MHC class I recognition. Immunology 115, 433-440. Takasu, M. A., Dalva, M. B., Zigmond, R. E. and Greenberg, M. E. (2002) Modulation of NMDA receptordependent calcium influx and gene expression through EphB receptors. Science 295, 491-495. Takuma, K., Fang, F., Zhang, W., Yan, S., Fukuzaki, E., Du, H., Sosunov, A., McKhann, G., Funatsu, Y., Nakamichi, N., Nagai, T., Mizoguchi, H., Ibi, D., Hori, O., Ogawa, S., Stern, D. M., Yamada, K. and Yan, S. S. (2009) RAGE-mediated signaling contributes to intraneuronal transport of amyloid-beta and neuronal dysfunction. Proceedings of the National Academy of Sciences of the United States of America 106, 20021-20026. Takuma, K., Yao, J., Huang, J., Xu, H., Chen, X., Luddy, J., Trillat, A. C., Stern, D. M., Arancio, O. and Yan, S. S. (2005) ABAD enhances Abeta-induced cell stress via mitochondrial dysfunction. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 19, 597-598. Talaga, P. and Quere, L. (2002) The plasma membrane: a target and hurdle for the development of anti-Abeta drugs? Current drug targets. CNS and neurological disorders 1, 567-574. Terzi, E., Holzemann, G. and Seelig, J. (1997) Interaction of Alzheimer beta-amyloid peptide(1-40) with lipid membranes. Biochemistry 36, 14845-14852. Tillement, L., Lecanu, L. and Papadopoulos, V. (2011) Alzheimer's disease: effects of beta-amyloid on mitochondria. Mitochondrion 11, 13-21. Tokuda, T., Calero, M., Matsubara, E., Vidal, R., Kumar, A., Permanne, B., Zlokovic, B., Smith, J. D., Ladu, M. J., Rostagno, A., Frangione, B. and Ghiso, J. (2000) Lipidation of apolipoprotein E influences its isoform-specific interaction with Alzheimer's amyloid beta peptides. The Biochemical journal 348 Pt 2, 359-365. Tooyama, I., Kawamata, T., Akiyama, H., Kimura, H., Moestrup, S. K., Gliemann, J., Matsuo, A. and McGeer, P.
Page 58 of 68
Ac ce pt e
d
M
an
us
cr
ip t
L. (1995) Subcellular localization of the low density lipoprotein receptor-related protein (alpha 2macroglobulin receptor) in human brain. Brain research 691, 235-238. Trouw, L. A., Nielsen, H. M., Minthon, L., Londos, E., Landberg, G., Veerhuis, R., Janciauskiene, S. and Blom, A. M. (2008) C4b-binding protein in Alzheimer's disease: binding to Abeta1-42 and to dead cells. Molecular immunology 45, 3649-3660. Tsigelny, I. F., Crews, L., Desplats, P., Shaked, G. M., Sharikov, Y., Mizuno, H., Spencer, B., Rockenstein, E., Trejo, M., Platoshyn, O., Yuan, J. X. and Masliah, E. (2008) Mechanisms of hybrid oligomer formation in the pathogenesis of combined Alzheimer's and Parkinson's diseases. PloS one 3, e3135. Udan, M. L., Ajit, D., Crouse, N. R. and Nichols, M. R. (2008) Toll-like receptors 2 and 4 mediate Abeta(1-42) activation of the innate immune response in a human monocytic cell line. Journal of neurochemistry 104, 524-533. Um, J. W., Nygaard, H. B., Heiss, J. K., Kostylev, M. A., Stagi, M., Vortmeyer, A., Wisniewski, T., Gunther, E. C. and Strittmatter, S. M. (2012) Alzheimer amyloid-beta oligomer bound to postsynaptic prion protein activates Fyn to impair neurons. Nature neuroscience 15, 1227-1235. Vazzana, N., Santilli, F., Cuccurullo, C. and Davi, G. (2009) Soluble forms of RAGE in internal medicine. Internal and emergency medicine 4, 389-401. Velayudhan, L., Killick, R., Hye, A., Kinsey, A., Guntert, A., Lynham, S., Ward, M., Leung, R., Lourdusamy, A., To, A. W., Powell, J. and Lovestone, S. (2012) Plasma transthyretin as a candidate marker for Alzheimer's disease. Journal of Alzheimer's disease : JAD 28, 369-375. Venkitaramani, D. V., Chin, J., Netzer, W. J., Gouras, G. K., Lesne, S., Malinow, R. and Lombroso, P. J. (2007) Beta-amyloid modulation of synaptic transmission and plasticity. The Journal of neuroscience : the official journal of the Society for Neuroscience 27, 11832-11837. Verdier, Y., Zarandi, M. and Penke, B. (2004) Amyloid beta-peptide interactions with neuronal and glial cell plasma membrane: binding sites and implications for Alzheimer's disease. Journal of peptide science : an official publication of the European Peptide Society 10, 229-248. von Ballmoos, C., Wiedenmann, A. and Dimroth, P. (2009) Essentials for ATP synthesis by F1F0 ATP synthases. Annual review of biochemistry 78, 649-672. Walker, D. G. and Lue, L. F. (2005) Investigations with cultured human microglia on pathogenic mechanisms of Alzheimer's disease and other neurodegenerative diseases. Journal of neuroscience research 81, 412425. Walter, S., Letiembre, M., Liu, Y., Heine, H., Penke, B., Hao, W., Bode, B., Manietta, N., Walter, J., SchulzSchuffer, W. and Fassbender, K. (2007) Role of the toll-like receptor 4 in neuroinflammation in Alzheimer's disease. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 20, 947-956. Wang, H. Y., Lee, D. H., D'Andrea, M. R., Peterson, P. A., Shank, R. P. and Reitz, A. B. (2000a) betaAmyloid(1-42) binds to alpha7 nicotinic acetylcholine receptor with high affinity. Implications for Alzheimer's disease pathology. The Journal of biological chemistry 275, 5626-5632. Wang, H. Y., Lee, D. H., Davis, C. B. and Shank, R. P. (2000b) Amyloid peptide Abeta(1-42) binds selectively and with picomolar affinity to alpha7 nicotinic acetylcholine receptors. Journal of neurochemistry 75, 1155-1161. Wang, H. Y., Li, W., Benedetti, N. J. and Lee, D. H. (2003) Alpha 7 nicotinic acetylcholine receptors mediate beta-amyloid peptide-induced tau protein phosphorylation. The Journal of biological chemistry 278, 31547-31553. Wang, H. Y., Stucky, A., Liu, J., Shen, C., Trocme-Thibierge, C. and Morain, P. (2009a) Dissociating betaamyloid from alpha 7 nicotinic acetylcholine receptor by a novel therapeutic agent, S 24795, normalizes alpha 7 nicotinic acetylcholine and NMDA receptor function in Alzheimer's disease brain. The Journal of neuroscience : the official journal of the Society for Neuroscience 29, 10961-10973. Wang, X., Su, B., Lee, H. G., Li, X., Perry, G., Smith, M. A. and Zhu, X. (2009b) Impaired balance of mitochondrial fission and fusion in Alzheimer's disease. The Journal of neuroscience : the official journal of the Society for Neuroscience 29, 9090-9103. Wang, X., Su, B., Siedlak, S. L., Moreira, P. I., Fujioka, H., Wang, Y., Casadesus, G. and Zhu, X. (2008) Amyloid-beta overproduction causes abnormal mitochondrial dynamics via differential modulation of mitochondrial fission/fusion proteins. Proceedings of the National Academy of Sciences of the United States of America 105, 19318-19323. Waschuk, S. A., Elton, E. A., Darabie, A. A., Fraser, P. E. and McLaurin, J. A. (2001) Cellular membrane composition defines A beta-lipid interactions. The Journal of biological chemistry 276, 33561-33568. Wati, H., Kawarabayashi, T., Matsubara, E., Kasai, A., Hirasawa, T., Kubota, T., Harigaya, Y., Shoji, M. and Maeda, S. (2009) Transthyretin accelerates vascular Abeta deposition in a mouse model of Alzheimer's disease. Brain pathology 19, 48-57.
Page 59 of 68
Ac ce pt e
d
M
an
us
cr
ip t
Webster, S. and Rogers, J. (1996) Relative efficacies of amyloid beta peptide (A beta) binding proteins in A beta aggregation. Journal of neuroscience research 46, 58-66. Wilhelmus, M. M., Otte-Holler, I., Wesseling, P., de Waal, R. M., Boelens, W. C. and Verbeek, M. M. (2006) Specific association of small heat shock proteins with the pathological hallmarks of Alzheimer's disease brains. Neuropathology and applied neurobiology 32, 119-130. Wilson, L. M., Pham, C. L., Jenkins, A. J., Wade, J. D., Hill, A. F., Perugini, M. A. and Howlett, G. J. (2006) High density lipoproteins bind Abeta and apolipoprotein C-II amyloid fibrils. Journal of lipid research 47, 755-760. Wisniewski, T., Castano, E. M., Golabek, A., Vogel, T. and Frangione, B. (1994) Acceleration of Alzheimer's fibril formation by apolipoprotein E in vitro. The American journal of pathology 145, 1030-1035. Wolf, B. B., Lopes, M. B., VandenBerg, S. R. and Gonias, S. L. (1992) Characterization and immunohistochemical localization of alpha 2-macroglobulin receptor (low-density lipoprotein receptorrelated protein) in human brain. The American journal of pathology 141, 37-42. Wood, S. J., Chan, W. and Wetzel, R. (1996) Seeding of A beta fibril formation is inhibited by all three isotypes of apolipoprotein E. Biochemistry 35, 12623-12628. Xie, L., Helmerhorst, E., Taddei, K., Plewright, B., Van Bronswijk, W. and Martins, R. (2002) Alzheimer's betaamyloid peptides compete for insulin binding to the insulin receptor. The Journal of neuroscience : the official journal of the Society for Neuroscience 22, RC221. Xiong, Y., Jing, X. P., Zhou, X. W., Wang, X. L., Yang, Y., Sun, X. Y., Qiu, M., Cao, F. Y., Lu, Y. M., Liu, R. and Wang, J. Z. (2013) Zinc induces protein phosphatase 2A inactivation and tau hyperphosphorylation through Src dependent PP2A (tyrosine 307) phosphorylation. Neurobiology of aging 34, 745-756. Yaar, M., Zhai, S., Pilch, P. F., Doyle, S. M., Eisenhauer, P. B., Fine, R. E. and Gilchrest, B. A. (1997) Binding of beta-amyloid to the p75 neurotrophin receptor induces apoptosis. A possible mechanism for Alzheimer's disease. The Journal of clinical investigation 100, 2333-2340. Yamada, K., Hashimoto, T., Yabuki, C., Nagae, Y., Tachikawa, M., Strickland, D. K., Liu, Q., Bu, G., Basak, J. M., Holtzman, D. M., Ohtsuki, S., Terasaki, T. and Iwatsubo, T. (2008) The low density lipoprotein receptor-related protein 1 mediates uptake of amyloid beta peptides in an in vitro model of the bloodbrain barrier cells. The Journal of biological chemistry 283, 34554-34562. Yamamoto, K., Shimada, H., Koh, H., Ataka, S. and Miki, T. (2013) Serum levels of albumin-amyloid beta complexes are decreased in Alzheimer's disease. Geriatrics & gerontology international. Yamamoto, T., Yamada, A., Watanabe, M., Yoshimura, Y., Yamazaki, N., Yoshimura, Y., Yamauchi, T., Kataoka, M., Nagata, T., Terada, H. and Shinohara, Y. (2006) VDAC1, having a shorter N-terminus than VDAC2 but showing the same migration in an SDS-polyacrylamide gel, is the predominant form expressed in mitochondria of various tissues. Journal of proteome research 5, 3336-3344. Yamauchi, K., Tozuka, M., Hidaka, H., Nakabayashi, T., Sugano, M., Kondo, Y., Nakagawara, A. and Katsuyama, T. (2000) Effect of apolipoprotein AII on the interaction of apolipoprotein E with betaamyloid: some apo(E-AII) complexes inhibit the internalization of beta-amyloid in cultures of neuroblastoma cells. Journal of neuroscience research 62, 608-614. Yan, S. D., Chen, X., Fu, J., Chen, M., Zhu, H., Roher, A., Slattery, T., Zhao, L., Nagashima, M., Morser, J., Migheli, A., Nawroth, P., Stern, D. and Schmidt, A. M. (1996) RAGE and amyloid-beta peptide neurotoxicity in Alzheimer's disease. Nature 382, 685-691. Yan, S. D., Fu, J., Soto, C., Chen, X., Zhu, H., Al-Mohanna, F., Collison, K., Zhu, A., Stern, E., Saido, T., Tohyama, M., Ogawa, S., Roher, A. and Stern, D. (1997) An intracellular protein that binds amyloidbeta peptide and mediates neurotoxicity in Alzheimer's disease. Nature 389, 689-695. Yan, S. D., Stern, D., Kane, M. D., Kuo, Y. M., Lampert, H. C. and Roher, A. E. (1998) RAGE-Abeta interactions in the pathophysiology of Alzheimer's disease. Restorative neurology and neuroscience 12, 167-173. Yan, S. D., Zhu, H., Zhu, A., Golabek, A., Du, H., Roher, A., Yu, J., Soto, C., Schmidt, A. M., Stern, D. and Kindy, M. (2000) Receptor-dependent cell stress and amyloid accumulation in systemic amyloidosis. Nature medicine 6, 643-651. Yan, Y. and Wang, C. (2007) Abeta40 protects non-toxic Abeta42 monomer from aggregation. Journal of molecular biology 369, 909-916. Yang, D. S., Smith, J. D., Zhou, Z., Gandy, S. E. and Martins, R. N. (1997) Characterization of the binding of amyloid-beta peptide to cell culture-derived native apolipoprotein E2, E3, and E4 isoforms and to isoforms from human plasma. Journal of neurochemistry 68, 721-725. Yao, J., Du, H., Yan, S., Fang, F., Wang, C., Lue, L. F., Guo, L., Chen, D., Stern, D. M., Gunn Moore, F. J., Xi Chen, J., Arancio, O. and Yan, S. S. (2011) Inhibition of amyloid-beta (Abeta) peptide-binding alcohol dehydrogenase-Abeta interaction reduces Abeta accumulation and improves mitochondrial function in a mouse model of Alzheimer's disease. The Journal of neuroscience : the official journal of the Society
Page 60 of 68
Ac ce pt e
d
M
an
us
cr
ip t
for Neuroscience 31, 2313-2320. Yazawa, H., Yu, Z. X., Takeda, Le, Y., Gong, W., Ferrans, V. J., Oppenheim, J. J., Li, C. C. and Wang, J. M. (2001) Beta amyloid peptide (Abeta42) is internalized via the G-protein-coupled receptor FPRL1 and forms fibrillar aggregates in macrophages. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 15, 2454-2462. Ye, S., Huang, Y., Mullendorff, K., Dong, L., Giedt, G., Meng, E. C., Cohen, F. E., Kuntz, I. D., Weisgraber, K. H. and Mahley, R. W. (2005) Apolipoprotein (apo) E4 enhances amyloid beta peptide production in cultured neuronal cells: apoE structure as a potential therapeutic target. Proceedings of the National Academy of Sciences of the United States of America 102, 18700-18705. Yoshiike, Y., Tanemura, K., Murayama, O., Akagi, T., Murayama, M., Sato, S., Sun, X., Tanaka, N. and Takashima, A. (2001) New insights on how metals disrupt amyloid beta-aggregation and their effects on amyloid-beta cytotoxicity. The Journal of biological chemistry 276, 32293-32299. Zabel, M., Schrag, M., Mueller, C., Zhou, W., Crofton, A., Petersen, F., Dickson, A. and Kirsch, W. M. (2012) Assessing candidate serum biomarkers for Alzheimer's disease: a longitudinal study. Journal of Alzheimer's disease : JAD 30, 311-321. Zatta, P., Bordin, C. and Favarato, M. (1993) The inhibition of trypsin and alpha-chymotrypsin proteolytic activity by aluminum(III). Archives of biochemistry and biophysics 303, 407-411. Zerbinatti, C. V. and Bu, G. (2005) LRP and Alzheimer's disease. Reviews in the neurosciences 16, 123-135. Zerbinatti, C. V., Wahrle, S. E., Kim, H., Cam, J. A., Bales, K., Paul, S. M., Holtzman, D. M. and Bu, G. (2006) Apolipoprotein E and low density lipoprotein receptor-related protein facilitate intraneuronal Abeta42 accumulation in amyloid model mice. The Journal of biological chemistry 281, 36180-36186. Zerbinatti, C. V., Wozniak, D. F., Cirrito, J., Cam, J. A., Osaka, H., Bales, K. R., Zhuo, M., Paul, S. M., Holtzman, D. M. and Bu, G. (2004) Increased soluble amyloid-beta peptide and memory deficits in amyloid model mice overexpressing the low-density lipoprotein receptor-related protein. Proceedings of the National Academy of Sciences of the United States of America 101, 1075-1080. Zhang, W., Wang, L. Z., Yu, J. T., Chi, Z. F. and Tan, L. (2012) Increased expressions of TLR2 and TLR4 on peripheral blood mononuclear cells from patients with Alzheimer's disease. Journal of the neurological sciences 315, 67-71. Zou, K., Gong, J. S., Yanagisawa, K. and Michikawa, M. (2002) A novel function of monomeric amyloid betaprotein serving as an antioxidant molecule against metal-induced oxidative damage. The Journal of neuroscience : the official journal of the Society for Neuroscience 22, 4833-4841.
Page 61 of 68
Table 1. Clinical trials targeting A-interacting molecules Table 1. Clinical trials targeting A-interacting molecules
Instituto Grifols, S.A Albumin
Instituto Grifols, S.A
RAGE
ApoE
Characterisitics A Study to Evaluate Albumin and Immunoglobulin in Alzheimer's Disease (AMBAR) Efficacy and Safety of Plasma Exchange With 5% Albutein in Beta-Amyloid Peptide Clearance in Cerebrospinal Fluid
Status
NCT number
Pfizer & Alzheimer's Disease A Phase 2 Study Evaluating The Efficacy And Safety Of Cooperative Study (ADCS) PF 04494700 In Mild To Moderate Alzheimer's Disease
Phase ൖ (Completed)
NCT00742417
Phase ൖ (Completed)
NCT00566397
MN Sabbagh et al (Alzheimer Dis Assoc Disord. 2011), Galasko D et al (Neurology. 2014)
vTv Therapeutics
Evaluation of the Efficacy and Safety of TTP488 in Patients With Mild Alzheimer's Disease
Phase ൗ (Recruiting)
NCT02080364
AH Burstein et al (BMC Neurol. 2014)
The Cleveland Clinic
Bexarotene Amyloid Treatment for Alzheimer's Disease (BEAT-AD)
Phase ൖ (Completed)
NCT01782742
Dai W et al (Neurodegener Dis. 2014), Aicardi G et al (Rejuvenation Res. 2013), etc.
NCT00608946
TA Bayer et al (Proc Natl Acad Sci USA. 2003), H Kessler et al (J Neural Transm. 2008)
Copper, Zinc
us
University Hospital, Saarland & Treatment With Copper in Patients With Mild Alzheimer´s Phase ൖ (Completed) University of Goettingen Dementia
Adeona Pharmaceuticals
Trial of Novel Oral Zinc Cysteine Preparation in Alzheimer's Disease
Prana Biotechnology Limited
Study Evaluating the Safety, Tolerability and Efficacy of PBT2 in Patients With Early Alzheimer's Disease
Phase ൖ (Completed)
NCT00471211
L Lannfelt et al (Lancet Neurol. 2008)
AbbVie
Evaluate the Efficacy and Safety of ABT-126 in Subjects Phase ൖ (Completed) with Mild to Moderate Alzheimer's Disease
NCT00948909
LM Gault et al (Alzheimers Dement. 2015)
an
Unknown
NCT01099332
M
7- nAchR
Relevant Publications
Phase ൖ & ൗ trial (Recruiting) NCT01561053
ip t
Company/Sponsors
cr
Molecules
Ac ce pt e
d
Data obtained from www.clinicaltrials.gov
Page 62 of 68
Ac ce pt e
d
M
an
us
cr
ip t
Figure 1. Diverse A-interacti A ing moleculles in differeent regions of body com mpartmentss
Abbrevviations: SA AP, serum amyloid a P componentt; ApoE, Apolipoprote A ein E; HDL L, highdensity lipoproteinn; RAGE, receptor r forr advanced d glycation end-produccts; TLR2, toll-like n; PrP, prion n protein; Ep EphB2, Ephrrin typereceptorr 2; LRP, lipoprotein receptor-relaated protein B recepptor 2; AP PP, amyloid precursoor protein; NMDA, N-methyl-D N D-aspartate; ERAB, endoplaasmic reticuulum-associiated amylooid beta; Ap poJ, Apolip poprotein J;; LilrB2, leeukocyte immunooglobulin-liike recepto or subfamilly B; 7nA AChR, alph ha-7 nicotinnic recepto or; SEC receptorr, serpin-ennzyme comp plex receptoor; p75NTR R, p75 neurotrophin receeptor
Page 63 of 68
Ac ce pt e
d
M
an
us
cr
ip t
Figure 22. A-binding membraane receptorrs in neuron and microg glia.
Abbrevviations: SEC receptor, serpin-enzzyme compllex receptorr; PirB, pairred Ig-like receptor B; p75N NTR, p75 neurotrophi n in receptor;; PrP, prion n protein; NMDA, N N-m methyl-D-asspartate; EphB2,, Ephrin typpe-B recepto or 2; 7nAC ChR, alpha--7 nicotinic acetylcholiine receptorr; RAGE, receptorr for advannced glycattion end-prooducts; TL LR2, toll-lik ke receptor 2; JNK, c-Jun c Nterminaal kinase; p38-MAPK, p , p38-mitoggen-activateed protein kinase; k NF--B, nucleaar factor kappa B B; PI3K, phhosphoinosittide 3-kinasse; ERK, ex xtracellular signal-regul s lated kinasees; PKC, protein kinase C; PYK2, P calciium sensitivve tyrosine kinase k 2
Page 64 of 68
Ac ce pt e
d
M
an
us
cr
ip t
Figure 33. Mitochonndrial A-biinding compponents
Abbrevviations: TO OM, translo ocase of thhe outer membrane; m ABAD, A A binding alcohol dehydroogenase; AN NT, adenine nucleotidde translocaator; hPreP, human preesequence protease; p VDAC,, voltage-deependent an nion channnel; Fis1, fission f proteein 1; Drp 1, dynamin n-related protein 1
Page 65 of 68
Abbreviation list.
AD: Alzheimer’s Disease A: amyloid beta
ip t
ADAS-Cog : Alzheimer’s Disease Assessment Scale-cognitive subscale MMSE: Mini-Mental State Examination
cr
ApoE: Apolipoprotein E
us
APP: amyloid precursor protein BBB: blood brain barrier
an
RXR: retinoid X receptor
PPAR: peroxisome proliferator-activated receptor gamma
M
LXR: liver X receptor ApoJ: apolipoprotein J
Ac ce pt e
HDL: high density lipoproteins
d
LRP: low-density lipoprotein receptor-related protein
SAP: serum amyloid P component PP2A: protein phosphatase 2A
RAGE: receptor for advanced glycation end products ERK: extracellular signal-related kinases NF-B: nuclear factor kappa B MMP: matrix metalloprotease
NMDA: N-methyl-D-aspartate
p75NTR: the 75-kD neurotrophin receptor TrkA: tyrosine kinase receptor A SEC receptor: serpin-enzyme complex receptor 7nAChR: 7 nicotinic acetylcholine receptor
Page 66 of 68
MAPK: mitogen-activated protein kinase PI3-k: phosphatidylinositol 3-kinase EphB2: ephrin type-B receptor 2 PrP: prion protein
ERAB: endoplasmic reticulum-associated A peptide binding protein
cr
PTB domain: phosphotyrosin-binding domain
mPTP: mitochondrial permeability transition pore
an
ABAD: A-binding alcohol dehydrogenase VDAC: voltage-dependent anion channel
d
Ac ce pt e
Drp1: dynamin related protein 1
M
ANT: adenine nucleotide translocase
hPreP: presequence protease
us
Hsp: heat shock protein
TOM: translocase of the outer membrane
ip t
LilrB2(PriB): leukocyte immunoglobulin-like receptor B2
Fis 1: fission protein 1
PreP: presequence protease TLR: toll-like receptor
MAP3K: mitogen-activated protein 3 kinases JNK: c-Jun N-terminal kinases
mFPR2: mouse G-protein coupled formyl peptide receptor M-CSF: macrophage-colony stimulating factor CAA: cerebral amyloid angiopathy PKC: protein kinase C PYK2: calcium sensitive tyrosine kinase SR: scavenger receptor
Page 67 of 68
Highlights
z A-interacting proteins in the blood and brain
z Intracellular A-binding proteins z Mitochondrial A-binding components
us
z A-interacting mediators of immune activation
cr
z A-binding membrane components (receptors)
ip t
z A-interacting metal ions
Ac ce pt e
d
M
an
z Other amyloidogenic proteins
Page 68 of 68
S0301-0082(15)30036-8 http://dx.doi.org/doi:10.1016/j.pneurobio.2015.12.004 PRONEU 1410
To appear in:
Progress in Neurobiology
Received date: Revised date: Accepted date:
25-6-2015 2-12-2015 9-12-2015
Please cite this article as: Han, S.-H., Park, J.-C., Mook-Jung, I.,Amyloid rmbeta-interacting partners in Alzheimer’s disease: From accomplices to possible therapeutic targets, Progress in Neurobiology (2015), http://dx.doi.org/10.1016/j.pneurobio.2015.12.004 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Amyloid -interacting partners in Alzheimer’s disease:
ip t
From accomplices to possible therapeutic targets
cr
us
Sun-Ho Han (Ph.D.), Jong-Chan Park (B.S.) and Inhee Mook-Jung (Ph.D.)*
an
Department of Biochemistry and Biomedical Sciences, Seoul National University,
M
College of Medicine, 28 Yungun-dong, Jongro-gu, Seoul 110-799, Korea
d
Ac ce pt e
*Corresponding Author:
Inhee Mook-Jung, Ph.D
Department of Biochemistry and Biomedical Sciences, Seoul National University, College of Medicine, 28 Yungun-dong, Jongro-gu, Seoul 110-799, Korea E-mail: [email protected]
Phone number: +82-2-740-8245 Fax number: +82-2-3672-7352
Total word count: 12,134
Page 1 of 68
Contents 1. Introduction 2. A-interacting proteins in the blood and brain
2.2. Apolipoprotein E
cr
2.3. A-interacting proteins in the cerebrospinal fluid 2.4. A-interacting proteins in the blood
us
3. Metal ions
ip t
2.1. Albumin
3.1 Copper
an
3.2 Zinc
M
3.3 Iron 3.4 Aluminium
d
3.5 Therapeutic strategy targeting metal ions
Ac ce pt e
4. A-binding membrane components (receptors) 4.1 Receptor for advanced glycation end products 4.2 Low-density lipoprotein-related protein 4.3 Prion protein
4.5 Ephrin type-B receptor2 4.6 Serpin-enzyme complex 4.7 Insulin receptor
4.8 Neurotransmitter receptors 4.9 Integrin 4.10 Leukocyte immunoglobulin-like receptor B2 4.11 Membrane lipids 4.12 Amyloid precursor protein
Page 2 of 68
5. Intracellular A-binding proteins 5.1 Endoplasmic reticulum-associated A-interacting proteins 5.2 Chaperone proteins
ip t
5.3 X11-llike, ˞B-crystallin and lysozyme 6. Mitochondrial A-binding components
cr
6.1 Cytochrome c oxidase
6.3 Mitochondrial permeability transition pore
us
6.2 A-binding alcohol dehydrogenase
an
7. 6.4 Mitochondrial enzymesA-interacting mediators of immune activation 7.1 Toll-like receptors
M
7.2 Receptor for advanced glycation end products
7.4 Microglial receptors
d
7.3 CD36
Ac ce pt e
8. Other amyloidogenic proteins 8.1 alpha-Synuclein 8.2 A40 and 42
8.3 Trnasthyretin
9. Conclusion
Acknowledgements References
Page 3 of 68
Abstract Alzheimer’s disease (AD) is one of the most devastating neurodegenerative diseases in modern society because of insurmountable difficulties in early diagnosis and lack of therapeutic treatments. AD pathogenesis is tightly linked to the abnormal accumulation and
ip t
aggregation of amyloid (A), seemingly the main causative factor of AD; however,
cr
intensive research on A has not yet explained the complexity of AD pathogenesis. Consequently, the role of other supportive partners of A have been elucidated and evaluated
us
in the etiology of AD, and their potential molecular mechanisms have emerged as possible therapeutic targets. In this review, we compile information regarding A-interacting partners
an
in normal conditions and AD pathology, and analyze their etiological roles in diverse areas.
M
Furthermore, we integrate this information into suggestions for probable clinical applications for AD diagnosis and therapeutics. We include A-interacting partners localized to the cell
d
surface and intracellular and extracellular compartments of different cell types ranging from
Ac ce pt e
the central nervous system to peripheral regions. Additionally, we expand the range of Ainteracting partners by including not only proteins, but also inorganic substances like metals, expecting that one of these partners may yield a critical breakthrough in the field of AD diagnostics and therapeutic drug development.
Key Words: Alzheimer’s disease, Amyloid , Amyloid -interacting protein, Blood brain barrier, cerebrospinal fluid
Page 4 of 68
1. Introduction Alzheimer’s disease (AD) is one of the most concerning neurodegenerative diseases in present society due to the lack of early diagnostic methods and therapeutic remedies. Amyloid β (A) plaques are regarded as the main etiological hallmark of AD. Plaque
ip t
formation begins with abnormal production or impaired clearance of A and consequent
cr
accumulation and aggregation, leading to formation of A plaques in the brain (Mawuenyega et al., 2010; Querfurth and LaFerla, 2010). Increased A levels are tightly associated with
us
synaptic dysfunctions and neuronal network perturbations, which are regarded as the main
an
cause of cognitive impairment in AD (Palop and Mucke, 2010). Contrary to AD, in other types of dementia aggregated forms of A are not present, suggesting that aggregation of Aβ
M
peptides is a peculiar characteristic of AD, and plays a pivotal role in its pathogenesis. Therefore, inhibition of A aggregation or its effects may be a key solution to prevent the
d
initiation of AD or slow down its etiological progression.
Ac ce pt e
Accumulating evidence suggests that A elicits its deleterious effects, including toxicity on cellular and synaptic functions, through binding to certain molecular partners. However, other molecules may interact with A and prevent the A-mediated toxic effects. Therefore, Ainteracting proteins and molecules are tightly associated with diverse aspects of AD pathophysiology. Firstly, numerous A-interacting proteins play a critical role in influencing the lifespan of A via regulating A generation, aggregation, disaggregation, and degradation (Bohrmann et al., 1999; Clinton et al., 2010; Hone et al., 2003). Certain A-interacting proteins are capable of modulating the amyloidogenic and catabolic process by interacting with A (Fagan et al., 2002; Ono et al., 2012). Other A-interacting proteins either enhance or inhibit A aggregation by maintaining A in a free or bound form, respectively (Clinton et al., 2010; Schwarzman and Goldgaber, 1996). This process is critical in AD pathogenesis, because abnormally accumulated A, usually the free form of A, aggregates to form
Page 5 of 68
neurotoxic A, whereas bound forms do not tend to aggregate (Bohrmann et al., 1999). Secondly, A-interacting partners, localized in both intra/extracellular compartments and on the cell surface, typically serve as mediators for A-triggered signaling (activation or inhibition) (Freir et al., 2011; Sturchler et al., 2008), which is closely linked to synaptic
ip t
dysfunction and neuronal toxicity. Thirdly, A directly binds to certain enzymes that are
cr
critical in cell dynamics, and modulates their activities and functions (Chen and Yan, 2007; Hernandez-Zimbron et al., 2012; Lustbader et al., 2004), which leads to the breakdown of
us
cellular homeostasis and further toxicity. A-interacting partners attract a great interest, as they might help in understanding the pathophysiology of AD, and therefore, comprehensive
an
assessment of A-interacting proteins and their diverse roles is necessary for developing
M
therapeutic agents for AD targeting these proteins. Careful investigation of A-interacting partners may provide valuable information to understand A-mediated cellular toxicity in AD
Ac ce pt e
these regulatory partners.
d
and promising first-line interventions to delay or prevent disease progression by modulating
2. A-interacting proteins in the blood and brain 2.1 Albumin
Albumin, a 65-kDa protein, is the most abundant protein in the serum, and binds toxic materials in the circulation, including A (Carter and Ho, 1994) (Fig. 1). Serum albumins bind the majority of serum A, sequestrating 90–95% of A in the blood, and therefore, very little free A exists in the blood (Biere et al., 1996; Kuo et al., 2000). In addition, albumin inhibits A polymerization through A/albumin interactions at physiological concentrations; thus, representing 60% of all A polymerization inhibitory activities among various plasma proteins (Bohrmann et al., 1999). Therefore, differences in albumin concentration between the serum (~640 M) and cerebrospinal fluid (CSF, 3 M) might explain why A plaques are
Page 6 of 68
deposited in the brain instead of peripheral tissues (Stanyon and Viles, 2012; Stevens et al., 1979). Level of serum albumin is tightly associated with cognitive impairment, as the elderly with low serum albumin levels have increased odds for impaired cognitive function after adjusting for possible risk factors such as age, sex, and education (Llewellyn et al., 2010).
ip t
Additionally, patients with AD exhibit significantly decreased serum albumin levels
cr
compared with control individuals (Maes et al., 1999), which supports a relationship between serum albumin levels and cognitive impairment. Notably, decreased levels of the albumin/A
us
complex in the serum is associated with an increased prevalence of AD (Yamamoto et al., 2013). Furthermore, a positive correlation between Mini-Mental State Examination (MMSE)
an
scores and decreased serum albumin levels in patients with AD suggests that serum albumin
M
levels are directly correlated with cognitive impairment during AD pathogenesis (Kim et al., 2006). Albumin may act on cognitive function in AD via the inhibition of A fibril growth,
d
which is achieved by both increasing the lag time for A fibrillization and decreasing the
Ac ce pt e
amount of free A, as the formation of amyloid fibers is directly proportional to the amount of the free A (Stanyon and Viles, 2012). Therefore, treatment with human albumin was attempted for patients with mild to moderate AD through plasma exchange to sequestrate free A and modulate the equilibrium between the albumin-bound and free form of A (Boada et al., 2009). Beneficial effects were observed in albumin-treated patients with regard to A40 mobilization and cognitive status scores, including MMSE and the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-Cog); thus, albumin could be a therapeutic target for AD. Additional studies and clinical trials are ongoing to investigate the therapeutic use of albumin and immunoglobulins in the treatment of AD (Costa et al., 2012) (Table 1). 2.2 Apolipoprotein E Apolipoprotein E (ApoE) exists in both the brain and blood. Numerous studies have investigated the binding of ApoE to A and its subsequent involvement in A clearance and
Page 7 of 68
aggregation (Fig. 1). Different ApoE isoforms, either free or lipid-associated forms, produce sodium dodecyl sulfate-resistant complexes with A according to their isoform-specific binding patterns to A (Aleshkov et al., 1997; LaDu et al., 1994; Sanan et al., 1994; Strittmatter et al., 1993b; Yang et al., 1997). ApoE interacts with the residues 12–28 of A,
ip t
and the isoform-specific efficacy for A binding is ApoE2 > ApoE3 > ApoE4 in lipidated
cr
conditions (Strittmatter et al., 1993a; Strittmatter et al., 1993b; Tokuda et al., 2000). This suggests that different binding capacities of various ApoE isoforms may result in different
us
degree of A clearance, which is supported by the increased risk for AD development in
an
ApoE epsilon 4 allele carriers. However, the consequences of ApoE/Aβ interactions are controversial, even though it is obvious that ApoE affects AD pathogenesis by modulating A
M
aggregation and clearance. Some reports suggest that interaction of ApoE and A, regardless of the ApoE isotype, promotes A fibrillization; however, apoE4 exhibits a particularly high
d
efficacy for inducing A fibrillization compared with ApoE2 and ApoE3 (Castano et al., 1995;
Ac ce pt e
Wisniewski et al., 1994). By contrast, other in vitro studies demonstrated that human ApoE isoforms decrease A fibrillization due to the inhibition of A nucleation formation (Webster and Rogers, 1996; Wood et al., 1996).
In vivo studies using mouse models of AD revealed that overexpression of different ApoE isoforms had various effects on AD neuropathogenesis by modulating A deposition and plaque formation (Fagan et al., 2002; Holtzman et al., 2000), and the ApoE4 isoform promotes the most prominent fibrillar A deposition. Besides their role in A deposition, both murine and human ApoE are crucial in regulating neuritic degeneration (Holtzman et al., 2000). Human ApoE isoforms are more beneficial for delaying A deposition than mouse ApoE molecules (Fagan et al., 2002), which is consistent with the finding that apoE levels are decreased in the serum of patients with AD, and this decrease correlates with disease severity as represented by the MMSE score (Han et al., 2014). The beneficial effects of human ApoE
Page 8 of 68
expression are also isoform-dependent, as human ApoE3 expression delayed synaptic deficits, while ApoE4 expression failed to protect against them (Buttini et al., 2002). Furthermore, amyloid plaque deposition was more prominent following ApoE4 expression compared with ApoE3 expression. In other study, ApoE knockout mice exhibit a significant decrease in A
ip t
deposition, neuritic dystrophy, and amyloid plaques (Bales et al., 1997; Holtzman et al., 2000;
cr
Holtzman et al., 1999).
In addition, ApoE is involved in A metabolism, including A production and clearance.
us
Although the isomer-specific involvement of ApoE in amyloid precursor protein (APP) processing remains controversial (Cedazo-Minguez et al., 2001; Ye et al., 2005), it is
an
conceivable that ApoE influences A clearance and metabolism through several mechanisms.
M
The connection between ApoE and A metabolism is supported by the ApoE-mediated decrease of soluble A levels, localization of A in membrane microdomains (Fagan et al.,
d
2002), and AD-related alterations of ApoE levels in the CSF and serum (Gupta et al., 2011;
Ac ce pt e
Han et al., 2014; Hesse et al., 2000). Lipidated ApoE can sequestrate A, and modulate either its cellular degradation by reuptake through receptor-mediated endocytosis or its systemic removal after crossing the blood brain barrier (BBB) (Jiang et al., 2008; Kim et al., 2009; Trouw et al., 2008; Yamauchi et al., 2000). Therefore, diverse ApoE-targeting therapeutic approaches have been attempted recently, such as increasing ApoE levels, increasing ApoE receptor expression, and modulation of ApoE/A interactions. Blocking A/ApoE interaction by non-toxic homologous to the binding motif within ApoE prevents brain A accumulation, neuritic degeneration and ameliorate memory deficit in AD model mice (Pankiewicz et al., 2014). Other study shows that A/ApoE interaction contributes to intraneuronal A accumulation, demonstrating increased A content using neurons/astrocyte co-culture system (Kuszczyk et al., 2013). In this study, blocking A/ApoE interaction using in vitro homologous and in vivo knockout mice inhibit intracellular A accumulation and loss of
Page 9 of 68
synaptic protein, which indicate possible therapy of modulating A/ApoE interaction. Transcriptional activation of ApoE expression by retinoid X receptor (RXR) agonists, most notably bexarotene (Targretin), a highly selective and BBB permeable RXR agonist, increases A clearance and microglial phagocytosis through the activation of peroxisome
ip t
proliferator-activated receptor gamma (PPAR) and liver X receptor (LXR) (Cramer et al.,
cr
2012). In a mouse model of AD, bexarotene reduces A levels in the cerebral interstitial fluid, cortex, and hippocampus; these levels correlate with the behavioral improvements and
us
bexarotene-mediated increases in ApoE expression. This suggests that a treatment targeting ApoE may be beneficial for the treatment of AD. Notably, bexarotene is currently undergoing
an
a phase 2 clinical trial (ClinicalTrials.gov identifier: NCT01782742, Table 1) for the
M
treatment of amyloid plaques in AD (Aicardi, 2013; Dai et al., 2014). However, controversial genetic studies also suggest that decreasing ApoE levels are beneficial in AD, proving
d
decrease A level, plaque formation and microglial activation by genetically manipulated
Ac ce pt e
reduction of ApoE level (Bien-Ly et al., 2012; Kim et al., 2011). Further studies are necessary to validate the function of ApoE in A metabolism in vivo and in vitro, because the effect of ApoE on A clearance is likely affected by diverse conditions including lipidation status, isomer type, inflammatory activation, and BBB integrity during AD pathogenesis. 2.3 A-interacting proteins in the cerebrospinal fluid Apolipoprotein J (apoJ, clusterin) is a sulfated glycoprotein present in most body fluids, and it binds to a diverse spectrum of molecules (Aronow et al., 1993; Calero et al., 2000; de Silva et al., 1990). Among its diverse ligands, ApoJ interacts with soluble A peptides in a 1:1 stoichiometry regardless of its lipidation status, and forms a stable complex under physiological conditions (Calero et al., 2000). This binding between A and apoJ is saturable, reversible, and of high affinity with a dissociation constant of 2ൈ10-9 M, which is not likely to be dissociated by other competitors such as ApoE, transthyretin, or 1-antichymotrypsin
Page 10 of 68
(Matsubara et al., 1995). Formation of the apoJ/A complex prevents the aggregation, polymerization, and fibrillization of A, which was proved by the co-incubation of A and apoJ. apoJ serves as the major A-binding protein in the CSF under normal conditions; however, the A binding propensity of apo proteins shifts during AD pathogenesis from apoJ
ip t
towards ApoE (Golabek et al., 1995). Besides the protective role of apoJ against A
cr
aggregation, apoJ is neuroprotective during cellular stress, and is upregulated to defend neurons against local damage after diverse insults including the pathological progression of
us
AD (Calero et al., 2000). Binding of apoJ and A accelerates the receptor-mediated cellular clearance of A from the brain by facilitating the binding of A to the low-density lipoprotein
an
receptor-related protein (LRP) 2/megalin (Hammad et al., 1997). In addition, apoJ can trigger
M
protective signaling cascades directly, which affect neurodegeneration and apoptosis, or activate the recovery systems regulating lipid transport or membrane recycling (Calero et al.,
d
2000). Furthermore, apoJ is co-localized with A fibrillary deposits and present in amyloid
Ac ce pt e
plaques and cerebrovascular amyloid deposits in the cortex and hippocampus of patients; however, it is not present in neurofibrillary tangles (Calero et al., 2000; McGeer et al., 1992). Increased mRNA and protein expression of apoJ is demonstrated in the hippocampus and cortex of the patients with AD, which implies a compensatory protective response during AD pathogenesis (Duguid et al., 1989; May et al., 1990; Oda et al., 1994). In contrast to the increase in apoJ levels in the AD brain, apoJ levels are decreased in the CSF, which might serve as a useful diagnostic biomarker (Puchades et al., 2003). Other A-binding proteins that exist at low concentrations show a mild reduction in their levels in the CSF during AD pathogenesis, including -trace/prostaglandin D2 synthase, cystatin C, 1-antitrypsin, and transthyretin (Hansson et al., 2009). Among them, reduction of 1-antitrypsin and transthyretin levels is AD-specific, while reduction in levels of the others is also shown in frontotemporal dementia. Positive correlations between the levels of A1-42
Page 11 of 68
and transthyretin, cystatin C, and -trace/prostaglandin D2 synthase in the CSF from AD suggest that deficient A-binding by partner proteins may influences the amyloidogenic pathway during AD pathogenesis (Hansson et al., 2009). 2.4 A-interacting proteins in the blood
ip t
In addition to albumin and ApoE, A interacts with diverse plasma proteins, including
cr
transthyretin, amyloid P component, 1-antichymotrypsin, and 2-macroglobulin (Du et al., 1997; Janciauskiene et al., 1998; Kalaria and Perry, 1993; Schwarzman et al., 1994) (Fig. 1).
us
Transthyretin is a 64-kDa homotetrameric protein synthesized in the choroid plexus; it is present in the CSF and serum(Sousa et al., 2007). Transthyretin binds and sequestrates A,
an
and subsequently inhibits Aβ aggregation and fibrillation in vitro (Schwarzman and
M
Goldgaber, 1996). The A binding domains of transthyretin were recently identified; strong binding is associated with residues 106–117 (strand G on the inner -sheet of transthyretin)
d
and a weak interaction at residues 59–83 (strand E through the E/F helix and loop) (Du et al.,
Ac ce pt e
2012). In another study, transthyretin was demonstrated to interact with, cleave, and degrade A aggregates (Costa et al., 2008). Furthermore, transthyretin levels in the CSF, serum, and plasma were altered significantly in the patients with AD, and the extent of decrease in plasma transthyretin levels correlates with the severity of AD pathology (Castano et al., 2006; Han et al., 2011a; Hansson et al., 2009; Velayudhan et al., 2012). Accordingly, increased transthyretin expression was suggested as one of the protective mechanisms against AD progression, because it might prevent plaque deposition and A-mediated neuronal toxicity in the brains of mice overexpressing APP with Swedish mutation (Stein and Johnson, 2002). These results indicate that transthyretin may have beneficial effects in both a diagnosis and therapeutic strategy in AD. Similar to transthyretin, 2-macroglobulin interacts with A, and prevents A fibril formation (Hughes et al., 1998). 2-Macroglobulin is the specific ligand for LRP, and promotes A
Page 12 of 68
clearance through LRP in cortical neurons (Chappell et al., 1992; Qiu et al., 1999). Interaction of A with 2-macroglobulin protease complexes increases A degradation, which may reduce the risk of AD development (Lauer et al., 2001). Notably, 2macroglobulin is one of the confirmed late onset genes leading to an increased risk for AD
ip t
(Blacker et al., 1998; Kovacs, 2000). Furthermore, elevated 2-macroglobulin levels in the
cr
blood of patients with AD validate the correlation between this A-interacting protein and AD pathogenesis (Hye et al., 2006; Zabel et al., 2012).
us
Similarly, 1-antichymotrypsin was reported to interact with A; however, its role in A aggregation is controversial. Certain studies suggest that 1-antichymotrypsin interacts with
an
A to stimulate A fibrillization in vitro and plaque deposition in a mouse model of AD (Ma
M
et al., 1994; Nilsson et al., 2001), while other studies reported that 1-antichymotrypsin inhibits A fibrillization and promotes disaggregation of A fibrils (Eriksson et al., 1995).
d
The exact functions and mechanisms of these interactions with A require further
Ac ce pt e
investigations; however, it is conceivable that interactions between A and plasma proteins affect the fate of A by modulating the aggregation process and clearance efficacy, which play critical roles in AD pathogenesis. Furthermore, AD-related alterations in the plasma levels of these interacting proteins could indicate disease progression and enable possible therapeutic interventions (Han et al., 2011a; Han et al., 2014; Velayudhan et al., 2012). Numerous blood proteins bind directly to A, and prevent the formation of A fibrils or accelerate A fibrillization. High density lipoproteins (HDL), including ApoA-I, ApoA-II, ApoE, clusterin, and serum amyloid A, are the main serum proteins that bind directly to A (Wilson et al., 2006). In the case of serum amyloid P (SAP), the literature is controversial. One study suggests that the component of SAP accelerates the formation of amyloid fibrils at unsaturated physiological concentrations of A42, and stabilizes the amyloid fibril (Mold et al., 2012), while another study proposes that SAP binds A peptides, inhibits fibril formation,
Page 13 of 68
and increases the solubility of Aβ (Janciauskiene et al., 1995).
3. Metal ions The relevance of metal ions in AD pathogenesis has been investigated in both the brain and
ip t
periphery in various studies. Metal ion homeostasis is perturbed drastically during AD
cr
pathogenesis, and diverse proteins crucial in AD pathology interact with transition metals. Notably, several metal ions affect A polymerization, nucleation, and plaque formation.
us
Recently, metal ions have been suggested to play a dual role in AD, which makes the
an
appreciation of metal ions complex and confusing in AD, with regard to both etiology and possible therapeutic strategies by utilizing metal chelators.
M
3.1 Copper
Copper (Cu) is one of the ions implicated in AD, and serum copper levels are higher in
d
patients with AD than in control subjects (Brewer et al., 2010) with a cutoff value of 16
Ac ce pt e
mol/L (Squitti et al., 2002). In the brain, Cu is concentrated in the extracellular compartment and in the amyloid plaques, which suggest the possibility of an interaction between Cu and A (Atwood et al., 1998; Lovell et al., 1998). However, it is controversial whether Cu/A interactions increase or inhibit A aggregation (Atwood et al., 1998; Faller, 2009; Raman et al., 2005). In addition to direct Cu/A interactions, even low levels of Cu modulate A production and clearance in the brain (Singh et al., 2013). In a mouse model of AD, Cu accumulates in the brain capillaries and parenchyma, and this accumulation is related to increased A production, neuroinflammation, and reduced A clearance through the downregulation of LRP1 (Singh et al., 2013). Furthermore, oxidative stress and neuronal toxicity, induced by hydrogen peroxide and toxic hydroxyl radicals, reduce Cu(II) to Cu(I) through Cu/A interactions (Hureau and Faller, 2009). Therefore, Cu affects A production, clearance, aggregation, and fibrillization through diverse mechanisms, either directly or
Page 14 of 68
indirectly. This is a strong evidence for the role of Cu in AD pathogenesis as an inorganic binding partner of A. Furthermore, several lines of evidence suggests that Cu binds not only to A, but also to tau, and thus exacerbates both amyloid and tau pathology in AD (Kitazawa et al., 2009; Ma et al., 2005; Martic et al., 2013).
ip t
3.2 Zinc
cr
Zinc (Zn) is distributed ubiquitously in the normal brain, and its level significantly increases in the brain (including the hippocampus and cortex) of patients with AD (Deibel et al., 1996;
us
Religa et al., 2006). Synaptic vesicular Zn levels are regulated by the transporter, ZnT3, which is essential for memory maintenance and normal cognitive function (Adlard et al.,
an
2010). Disturbed synaptic Zn levels in the ZnT3 knockout mice induce a significant decrease
M
in key synaptic proteins and synaptic density in the hippocampus, and cause age-dependent deficits in learning and memory, and thus might phenocopy AD. Ever since Zn levels were
d
found to be significantly higher in the serum and hippocampus of patients with AD than in
Ac ce pt e
controls (Danscher et al., 1997; Rulon et al., 2000), Zn has attracted much attention, as it was also reported to bind to A directly via a special binding site at the hydrophilic region of the N-terminus (Kozin et al., 2001). Similar to Cu or other A-interacting proteins, Zn is enriched in amyloid plaques and concentrated in the blood cells of patients with AD, and Zn/A interaction facilitates A aggregation (Mantyh et al., 1993; Suh et al., 2000). Interestingly, Zn is also involved in tau pathology by increasing tau hyperphosphorylation and aggregation (Sun et al., 2012; Xiong et al., 2013). Zn inactivates protein phosphatase (PP) 2A and induces tau hyperphosphorylation through the Src-dependent phosphorylation of PP2A at Y307 (Xiong et al., 2013). Zn was reported to elicit biphasic effects by initiating deleterious A deposition, redirecting A deposition towards amorphous aggregation, and quenching oxidative stress (Cuajungco and Faget, 2003; Huang et al., 2000; Rezaei-Ghaleh et al., 2011). Similarly, Cu/A
Page 15 of 68
complexes mediate cellular toxicity through oxidative mechanisms while they play a protective role by preventing the formation of amorphous aggregates from forming toxic fibril (Cuajungco and Faget, 2003; Suzuki et al., 2001; Yoshiike et al., 2001). Possibly, dual effects of metal ions on A-induced toxicity may occur in an A aggregation status dependent
ip t
manner, because A monomers sequestrate metal ion-induced oxygen radicals and protect
cr
neurons, whereas A aggregates induce the formation of oxygen radicals and neuronal death (Hou and Zagorski, 2006; Zou et al., 2002). Bifunctional compounds with binding motifs to
us
both metal (Cu, Zn) and A is used to inhibit the metal-mediated A42 aggregation and disaggregates amyloid fibrils (Sharma et al., 2012). Unexpectedly, increased formation of
an
neurotoxic soluble A42 due to inhibition of A aggregation and fibril disaggregation
be the simple answer in AD.
d
3.3 Iron
M
increases cellular toxicity, which apply therapeutic strategy to inhibit A aggregation may not
Ac ce pt e
In contrast to the extracellular localization of Cu and Zn, iron (Fe) is accumulated intracellularly during AD pathogenesis, leading to oxidative injury and neurodegeneration through redox-generated free radicals (Bush, 2013; Smith et al., 1997). Ferroxidase activity of the neuronal ferroxidase APP, which interacts with ferroportin to export Fe from the cells, is decreased in AD via the inhibition of Zn in the extracellular amyloid mass. Therefore, there is a pathological correlation between intracellular Fe accumulation and extracellular Zn deposition in the amyloid plaques (Bush, 2013; Duce et al., 2010; Smith et al., 1997). Fe binds to the first 16 amino acid residues of A at physiological pH (Bousejra-ElGarah et al., 2011), and redox-active Fe evokes A toxicity by causing cellular oxidative stress and lipid oxidation (Rottkamp et al., 2001). Furthermore, Fe binds to tau neurofibrillary tangles, and induces oxidative stress depending on the microenvironmental redox balance (Sayre et al., 2000). Tau maintains intracellular Fe levels by regulating APP trafficking and modulating the
Page 16 of 68
ferroxidase activity of APP; therefore, cognitive impairment and parkinsonism caused by brain atrophy and Fe accumulation in the tau KO mice are completely rescued by treatment with the Fe chelator clioquinol (Bush, 2013; Lei et al., 2012). 3.4 Aluminium
ip t
Aluminium (Al) is also a suspected risk factor for AD and the enhancement of A
cr
aggregation via its direct influence on aggregation and deposition processes (Kawahara et al., 1994; Neri and Hewitt, 1991). The presence of Al induced the conformational transition of
us
A40 from -helical to a -sheet and also AlATP enhanced the formation of thioflavin T reactive A fibrils with a -pleated sheet conformation (Exley and Korchazhkina, 2001;
an
Exley et al., 1993; House et al., 2004). Unlike Cu or Zn, Al and Fe directly influence the
M
precipitation of A -sheets, and the combination of these metals with the -sheets of A promotes oxidative neurotoxicity and neurodegeneration (Exley, 2006). Al-induced AD-
d
related neurotoxicity might be initiated by the modulation of anabolism and catabolism for
Ac ce pt e
APP and A and by increasing the formation of A and ubiquitin in neurons (Banks et al., 1996; Campbell et al., 2000; Exley, 2005; Korchazhkina et al., 2002). Al inhibits several proteases including the serine protease plasmin, which cleaves A, and therefore, it might inhibit the A degradation activity of plasmin (Clauberg and Joshi, 1993; Korchazhkina et al., 2002; Zatta et al., 1993).
3.5 Therapeutic strategy targeting metal ions Therapeutic candidates for AD targeting metal ions in the brain have been actively tested. The strategy of this AD therapy is to modulate the interaction between A and metal ions and to redistribute metal ions in the brain. Because Al or Fe initiates and stabilizes the assembly of the -pleated amyloid form, chelation of these metal ions would be beneficial to prevent the formation of A fibrils (House et al., 2004). Similarly, treatment with chelators that bind bioavailable Cu or Zn, such as clioquinol and PBT2, decreased A deposits and increased
Page 17 of 68
soluble A levels in a mouse model of AD (Cherny et al., 2001), and significantly improved cognitive function in a randomized, double-blinded, placebo-controlled Phase IIa clinical trial (Faux et al., 2010; Lannfelt et al., 2008). Clioquinol and PBT2 have multi-mechanistic actions, including competition for metal ions against Aβ, and activation of cellular protective
ip t
signaling pathways by increasing the intracellular levels of these metals, as these
cr
chelator/metal complexes are easily transported across membranes (Crouch and Barnham, 2012). However, complexity of metal ion dynamics during AD pathogenesis will be the main
us
challenge in clinical trials testing therapeutic candidates targeting Cu or Zn in AD (Bayer et
an
al., 2003; Kessler et al., 2008; Lannfelt et al., 2008) (Table 1). Furthermore, considering the effects of other metal ions relevant to AD pathogenesis, including Fe and Al, dynamics of
M
various metal ions can influence not only the aggregation and metabolism of A, but also tau
d
activity during AD pathogenesis in parallel, which requires further studies.
Ac ce pt e
4. A-binding membrane components (receptors) To elicit their physiological functions, diverse forms of A need to interact with membrane proteins to signal towards intracellular compartments or to be internalized during AD pathogenesis. Probing into these events is regarded as one of the most promising ways to prevent AD or delay its pathological progression. Therefore, it is critical to understand the cellular membrane proteins that bind A, and their expression levels and propensities to interact with A to initiate cellular downstream signaling (Fig. 2). 4.1 Receptor for advanced glycation end products Receptor for advanced glycation end products (RAGE) is a single transmembrane protein that binds to multiple ligands. Ever since RAGE was reported as the cellular membrane receptor of A, RAGE-mediated cellular signaling and its consequences have attracted much attention,
Page 18 of 68
as they are especially relevant to AD pathology (Han et al., 2011b; Yan et al., 1996; Yan et al., 2000). RAGE interacts with diverse forms of A including monomeric, oligomeric, and fibrillar forms (Sturchler et al., 2008; Verdier et al., 2004); however, the oligomeric form of A activates RAGE to a greater extent than the monomer form, and initiates inflammation
ip t
and tissue damaging processes (Herold et al., 2007). Kinetic studies demonstrated that
cr
RAGE/A interaction is fairly specific with Kd values ranging from 40 to 57 nM in different cell types (Yan et al., 1998). Additionally, RAGE/A interaction is dependent upon the
us
aggregation status of A and the binding sites in RAGE. The examination of RAGE binding sites using different forms of A and various inhibitors indicated that the Vd domain of
an
RAGE is responsible for A oligomer-induced apoptosis in SHSY-5Y cells and rat cortical
(Sturchler et al., 2008).
M
neurons, whereas the C1d domain of RAGE is involved in A aggregate-induced apoptosis
d
Depending on cell types or structures, such as cerebral vessels, microglia, and neurons,
Ac ce pt e
diverse ligands activate RAGE and thus various downstream signaling events including oxidative stress, activation of extracellular signal-related kinases (ERK), p38, and nuclear factor kappa B (NF-B) (Bianchi et al., 2007; de Arriba et al., 2003; Han et al., 2011b; Huttunen et al., 1999; Origlia et al., 2008; Poelmans et al., 2011; Riehl et al., 2009; Taguchi et al., 2000; Vazzana et al., 2009; Yan et al., 1996) (Fig. 2). The RAGE/A interaction induces cellular dysfunction and cytotoxicity through different signaling events, including oxidative stress and ERK activation, and is involved in mitochondrial dysfunction, neuronal toxicity, and synaptic dysfunction induced by increased A generation, intracellular transport, and RAGE expression (Arancio et al., 2004; Cho et al., 2009; Origlia et al., 2008; Takuma et al., 2009; Yan et al., 1996). Notably, elevated RAGE expression in neurons and microglia of animal models of AD and patients with AD implies that RAGE/A interaction may act as positive feedback mechanism during AD progression (Choi et al., 2014; Yan et al., 1998).
Page 19 of 68
Furthermore, RAGE overexpression increases the amount of A deposits and plaques clearly demonstrating the deleterious effect of this membrane receptor in the pathological progression of AD (Cho et al., 2009). Besides acting as a mediator of A-induced neuronal toxicity, RAGE serves as the primary
ip t
route for A to cross the BBB and enter the brain, which plays a critical role in AD
cr
pathogenesis (Deane et al., 2003; Deane and Zlokovic, 2007; Mackic et al., 1998; Yan et al., 1996). Peripheral A levels greatly impact A level and clearance in the central nervous
us
system; therefore, expression level and function of RAGE in the BBB is a crucial factor for
an
regulating cerebral Aβ levels (Marques et al., 2009; Sutcliffe et al., 2011). RAGE/A interactions result in the translocation of peripheral A into the brain across the BBB to
2003). Therefore, blockade of RAGE
M
increase cerebral A levels (Deane et al., 2003; Kawarabayashi et al., 2001; Matsuoka et al., in the BBB using a specific RAGE inhibitor (FPS-
d
ZM1) inhibits circulating A 40 and 42 to enter the brain, and therefore rescues from
Ac ce pt e
cognitive impairment caused by increased A40 and 42 levels in a mouse model of AD (Deane et al., 2012). Specifically, a region-specific inhibitor of RAGE may selectively antagonize a specific form of A and block a particular signaling cascade that is harmful to neurons. Additionally, interaction of A and RAGE in the BBB induced the expression of proinflammatory cytokines and endothelin-1, which might influence AD pathophysiology (Deane et al., 2003). Furthermore, another study reported that interaction of A and RAGE in cerebral endothelial cells disrupts the tight junctions in the BBB through the Ca2+-calcineurin signaling pathway, alters the integrity of microvessels close to the A plaques, and increases endothelial RAGE expression and matrix metalloprotease (MMP) secretion in a mouse model of AD (Kook et al., 2012). In addition, clinical trials for RAGE inhibitors are under investigation, including the phase III trial of TTP488 and the completed phase II trial for the oral inhibitor PF-04494700 (Burstein et al., 2014; Galasko et al., 2014; Sabbagh et al.,
Page 20 of 68
2011)(ClinicalTrials.gov identifier: NCT02080364, NCT00566397, Table 1). Therefore, RAGE regulates the cerebral A levels through diverse mechanisms. 4.2 Low-density lipoprotein receptor-related protein Low-density lipoprotein receptor-related protein (LRP) is a endocytic transmembrane
ip t
receptor with multi-ligand binding, belonged to low-density lipoprotein receptor (LDLR)
cr
family (Zerbinatti and Bu, 2005). LRP is expressed in the endothelial cells of the brain, and mediates rapid ligand endocytosis and signal transduction (Herz and Marschang, 2003; Herz
us
and Strickland, 2001; Shibata et al., 2000). Even though RAGE is the primary transporter of A across the BBB into the brain, accumulating evidence supports that LRP interacts with A
an
and is involved in the clearance of cerebral A by the endocytosis/transcytosis of A across
M
the BBB out of the brain (Deane et al., 2004; Donahue et al., 2006; Shibata et al., 2000). This LRP/A interaction and following LRP-dependent A was demonstrated in cellular context
d
of BBB, not in other cell types including fibroblasts or neuroblastoma cells expressing LRP1
Ac ce pt e
(Yamada et al., 2008). Accordingly, there is an increased expression of RAGE within the microvasculature of the hippocampus in AD compared to that in normal controls. By contrast, minimal LRP staining is observed in brains with AD, and this reduced expression correlates with regional A accumulation in such brains (Donahue et al., 2006; Shibata et al., 2000). In astrocyte, low-density lipoprotein receptor (LDLR) expressed mediate A uptake and degradation by direct interaction between LDLR and A, regardless of the presence of A (Basak et al., 2012). LDLR regulates brain A levels and the overexpression of LDLR could enhance A transport to lysosomes and promotes A degradation. LRP is also expressed in the neurons of the cortex and hippocampus (Bu et al., 1994; Tooyama et al., 1995; Wolf et al., 1992). LRP also mediates the neuronal A uptake and clearance in both a direct and indirect manner (Bu et al., 1994; Fuentealba et al., 2010; Tooyama et al., 1995). Receptor-mediated endocytosis is suggested as one of the neuronal
Page 21 of 68
mechanisms for A clearance by LRP1 (Kanekiyo et al., 2013). Conditional knockout of LRP1 exacerbate brain A levels and plaque deposition in cortex of APP/PS1 mice. Neuronal deletion of LRP1 in mice forebrain causes the breakdown of brain lipid homeostasis leading to dendritic spine loss, synaptic degeneration, memory loss, and finally neurodegeneration
ip t
(Liu et al., 2010). However, there are conflicting results on in vivo LRP study using LRP-
cr
overexpressing transgenic mice. Overexpression of LRP1 in the brain of PDAPP mice results in the increased soluble brain A (monomers/dimers), but not A plaque, which is
us
significantly related to spatial learning and memory deficit (Zerbinatti et al., 2004). Also followed study demonstrates that LRP1 overexpression in PDAPP mice increases membrane-
an
associated A 42 and intraneuronal A42 in the region of hippocampus or frontal cortex
M
(Zerbinatti et al., 2006). In addition, LRP influences the prion protein mediated toxicity of A oligomers by modulating cell surface interactions, the internalization process, and spreading
Ac ce pt e
4.3 Prion protein
d
of intracellular toxicity mediated by A oligomers (Rushworth et al., 2013).
Prion protein (PrP) has been recently identified as a critical high affinity receptor for toxic A assemblies that mediates diverse downstream toxic events including impairments in synaptic plasticity, memory, and neuronal survival (Alier et al., 2011; Bate and Williams, 2011; Gimbel et al., 2010; Kudo et al., 2012; Lauren et al., 2009). Inhibition of long term potentiation (LTP) by A occurs in a PrP-dependent manner (Freir et al., 2011), and is mediated by A protofibrils with a triple helical nanotube structure, rather than by the monomer or oligomer forms, while A fibrils inhibit LTP in a PrP-independent manner (Nicoll et al., 2013). Considering downstream signaling, soluble A assemblies interact with cellular PrP, and this event activates Fyn, which phosphorylates the NR2B subunit of Nmethyl-D-aspartate (NMDA) receptors, and relocalizes NMDA receptors, leading to neuronal impairments (Um et al., 2012) (Fig. 2). The process also results in dendritic spine loss and
Page 22 of 68
lactate dehydrogenase release after an initial increase of NMDA receptors, followed by the loss of these receptors. Therefore, anti-cellular PrP monoclonal antibodies are suggested as a new potential therapy for AD, because these antibodies improve behavioral effects of AD in a
prevent LTP inhibition and PrP/A interaction (Freir et al., 2011).
cr
4.4 Ephrin type-B receptor2
ip t
mouse model (Chung et al., 2010), and specific antibodies against helix-1 of PrP effectively
The receptor tyrosine kinase Ephrin type-B receptor2 (EphB2) is closely related with synaptic
us
function, including LTP, by modulating the NMDA-dependent Ca2+ influx and downstream transcription factors (Benilova and De Strooper, 2013; Henderson et al., 2001; Takasu et al.,
an
2002) (Fig. 2). The reduction of hippocampal EphB2 level was detected in transgenic mice
M
expressing the human APP and in the postmortem tissue from AD patients compared with non-transgenic controls and non-demented controls, respectively, suggesting the clinical
d
relevance of EphB2 in AD pathogenesis (Cisse et al., 2011; Simon et al., 2009). A
Ac ce pt e
oligomers bind directly to EphB2, and increase the proteasomal degradation of EphB2, which is another key factor of the A-mediated inhibition of LTP and subsequent memory impairment (Cisse et al., 2011; Simon et al., 2009). Increased levels of EphB2 in the dentate gyrus of mice that model AD reversed not only the impairment of NMDA receptor mediated LTP, but also memory decline (Cisse et al., 2011). 4.5 75-kD neurotrophin receptor
The 75-kD neurotrophin receptor (p75NTR), which leads to neuronal death in AD, is another receptor for specific A interactions (Yaar et al., 1997). A activates p75NTR, but not Trk, and mediates the downstream activation of the intracellular death domain of p75NTR and JNK phosphorylation, which induces apoptosis in hippocampal neurons (Diarra et al., 2009; Dinamarca et al., 2012). Similarly, p75NTR enhances A generation via the -cleavage of APP, while tyrosine kinase receptor A (TrkA), another neurotrophin receptor, reduces APP
Page 23 of 68
cleavage. A generation is increased in the brain during normal aging, which results from the upregulation of p75NTR signaling by switching from the TrkA-mediated signaling to the p75NTR-mediated signaling (Yaar et al., 1997). 4.6 Serpin-enzyme complex
ip t
The serpin-enzyme complex (SEC) receptor is a transmembrane protein expressed on diverse
cr
cell types, and is identified as a receptor for 1-antitrypsin/elastase complexes (Joslin et al., 1992). Soluble A interacts specifically with the SEC receptors in hepatoma and neuronal
us
cells, and SEC receptors mediate the internalization and metabolism of A (Boland et al., 1995). Amino acid residues 31-35 of the A peptide are identified as the critical region for the
an
association of SEC receptor and A. Inability of the SEC receptor to bind the aggregated
M
form of A, such as A fibrils, implies that this receptor exerts beneficial effects, including
al., 1996; Verdier et al., 2004).
Ac ce pt e
4.7 Insulin receptor
d
A clearance, rather than mediating the cytotoxic effects induced by fibrillar A (Boland et
It is not surprising that A binds directly to the insulin receptor, because insulin and A shares many common features including their consensus sequence, which serves as the substrate for insulin-degrading enzymes (Kurochkin, 1998; Xie et al., 2002). A competes with insulin for binding to the insulin receptor (A: 16-26 amino acid residues, insulin: 21-30 amino acid residues), and inhibits the action of insulin, which is tightly linked to insulin resistance caused by the excessive amount of A during AD pathogenesis. In addition, A blocks insulin receptor signaling directly by inhibiting the autophosphorylation of the insulin receptor (Ling et al., 2002). 4.8 Neurotransmitter receptors Numerous neurotransmitter receptors bind A, and these associations play a critical role in neuronal function and the neurodegenerative pathophysiology of AD. The 7 nicotinic
Page 24 of 68
acetylcholine receptor (7nAChR) is a neuronal pentameric cation-selective channel complex modulating the permeability of Ca2+ and Na+ (Breese et al., 1997; Verdier et al., 2004). It is an integral membrane protein, which is highly expressed in basal cholinergic neurons projecting to the hippocampus and cortex (Breese et al., 1997). A and 7nAChR can be co-
ip t
immunoprecipitated, and both are found in neuritic plaques in the brains of patients with AD
cr
(Wang et al., 2000a). The consequence of the 7nAChR/A interaction is still controversial; both agonist- and antagonist-like effects are suggested (Dougherty et al., 2003; Liu et al.,
us
2001). Agonist-like effects are observed in the presynaptic nAChRs inducing a sustained increase in Ca2+ levels at the presynaptic terminals (Dougherty et al., 2003; Mehta et al.,
an
2009), while other studies demonstrated that A inhibits neuronal 7nAChRs in rat
M
hippocampal slices and cultures (Liu et al., 2001; Pettit et al., 2001), and prevents the Ca2+ influx in synaptosomes (Lee and Wang, 2003; Wang et al., 2009a). It has been shown recently
d
that the agonistic effect of A on the 7nAChRs in presynaptic nerve terminals is mediated
Ac ce pt e
by receptor-associated lipid rafts (Khan et al., 2010). Similarly, tau phosphorylation is stimulated by the interaction of A and 7nAChRs (Wang et al., 2003). The binding affinity between A42 and 7nAChR is exceptionally high, within the picomolar concentration range, which suggests that this interaction might serve as a precipitating factor in amyloid plaque formation contributing to the degeneration of cholinergic neurons (Wang et al., 2000b). A binds and blocks 7nAChR reversibly through the extracellular N-terminal domain of the receptor, which is a non-competitive and voltage/use-independent process (Liu et al., 2001). Recent clinical study of the novel 7nAChR agonist, ABT-126, has suggested a promising result (Gault et al., 2015) and this kind of 7nAChR agonist may show their effectiveness through dual mechanism of receptor stimulation and blocking of A binding (Table 1). The NMDA receptor is another neurotransmitter receptor that interacts with A, and this binding influences synaptic function (Danysz and Parsons, 2012). Co-immunoprecipitation
Page 25 of 68
studies revealed that the interaction between NR1 or NR2A and soluble A oligomers in present in excitatory pyramidal neurons, but not in GABAergic neurons, and the interaction induces synaptic loss (Lacor et al., 2007; Venkitaramani et al., 2007). Binding of A to the NMDA receptor influences the internalization and pathogenic effect of A, which is blocked
ip t
by NMDA receptor antagonists (Bi et al., 2002). Selective NMDA receptor antagonists
cr
inhibit not only the internalization of A, but also the upregulation of cathepsin D and microglial activation. Similarly, oxidative stress induced by A application in vivo is
us
ameliorated by NMDA receptor antagonists (Parks et al., 2001). A activates NF-B through the NMDA receptor and via activation of the NMDA-Src-Ras-like protein, mitogen-activated
an
protein kinase (MAPK), and phosphatidylinositol 3-kinase (PI3-k) signaling pathway in
M
cultured cerebellar cells, which is regarded neuroprotective in response to A (Kawamoto et
related to the integrins.
Ac ce pt e
4.9 Integrin
d
al., 2008). Furthermore, in terms of A internalization, function of NMDA receptors is tightly
Integrins are heterodimers compiled of and glycoprotein transmembrane subunits, and they are related to the uptake of microorganisms such as bacteria and virus. Integrins bind directly to A, and cooperate with NMDA receptors to regulate A internalization (Bi et al., 2002; Isberg and Tran Van Nhieu, 1994). As mentioned above, NMDA receptor antagonists completely block A internalization, cathepsin D upregulation, and microglia activation, while antagonists of integrins enhance these phenomena; thus, suggesting that these two receptors work cooperatively during A internalization. In particular, fibronectin receptor 51 is highly expressed in the hippocampus, and mediates the internalization of non-fibrillar A by binding to the Arg-Gly-Asp (RGD)-like sequence of A, and thus enhances A clearance (Ghiso et al., 1992; Matter et al., 1998; Sabo et al., 1995). Therefore, 51 has a protective effect against A deposition/fibrillization, A-mediated toxicity, and apoptosis.
Page 26 of 68
4.10 Leukocyte immunoglobulin-like receptor B2 Besides PrP and EphB2, leukocyte immunoglobulin-like receptor B2 (LilrB2; paired immunoglobulin-like receptor B, PirB, in mice) has recently been found to bind A oligomers directly, and is involved in memory loss and the impairment of synaptic plasticity in a
ip t
transgenic model of AD (Kim et al., 2013). PirB (LilrB2) is a typical receptor of the
cr
immunoglobulin-like receptor family, and was originally thought to be expressed in a wide range of immunogenic cell types including B cells, mast cells, dendritic cells, and
us
macrophages (Takai, 2005). In the immune system, PirB inhibits receptor-mediated activation signals by interacting with other activating receptors. In addition, it contributes to major
an
histocompatibility complex (MHC) recognition (Takai, 2005). Recently, PirB has been found
M
in neurons and synapses (Atwal et al., 2008; Syken et al., 2006). Similar to EphB2, PirB inhibits LTP, alters synaptic plasticity, and induces behavioral impairments in a mouse model
d
of AD through the direct binding of PirB and A oligomers; these alterations can be rescued
Ac ce pt e
by PirB deletion (Kim et al., 2013). The downstream mechanism for the PirB/A oligomer interaction involves cofilin recruitment and activation by phosphorylation in an Adependent manner, as demonstrated in vitro and in vivo. Furthermore, alterations in cofilin phosphorylation are detected in patients with AD, which implies an AD-related role for PirB/A oligomer interaction. 4.11 Membrane lipids
A interacts not only with membrane-bound receptors, but also with the cell membrane directly. A interacts with the plasma membrane and membrane of subcellular organelles including the Golgi complex, lysosomes, and endoplasmic reticulum (Terzi et al., 1997; Waschuk et al., 2001). These interactions influence the properties (fluidity and structure) and function of the membrane through releasing lipid molecules from the neuronal plasma membrane, A fibrillogenesis, and abnormal Ca2+ entry into the cell through amyloid
Page 27 of 68
channels (Talaga and Quere, 2002). A has limited solubility in aqueous solutions, its structure is transformed into sheets at an acidic pH, and it binds electrostatically to the outer region of the polar head group of the membrane, but does not penetrate the polar groups (Terzi et al., 1997). Similarly, A binding studies using surface plasmon resonance revealed
ip t
that a large proportion of A is bound to membrane lipids, and this interaction disrupts the
cr
lipid structure and fluidity of the membrane, which might influence the localization and function of various receptors and channels on the cell membrane (Small et al., 2007). Lipid
us
compositions of different membranes influence A aggregation (Waschuk et al., 2001). A fibrillogenesis is accelerated in the presence of plasma lipid vesicles as fiber bundles along
an
the bilayer, driven by the interaction of A with the lipid surface. However, interaction of A
M
with the Golgi membrane does not enhance A fibril formation; it increases membrane fluidity through possible stabilization of A by the interaction between A and lipid head
d
groups in the Golgi and induction of interfacial packing defects. Furthermore, the lipid
Ac ce pt e
composition of the membrane, including the presence of gangliosides and cholesterol, plays a critical role in amyloid formation, because GM-1 ganglioside accelerates A fibril formation by binding Aβ possibly serving as seed (Kakio et al., 2002). In the other hand, soluble form of Aβ oligomers are sequestered and bound to GM1 ganglioside on brain membranes, more rapidly compared to monomer (Hong et al., 2014). This interaction between Aβ oligomer and GM-1 ganglioside has a critical role in Aβ–mediated synaptic dysfunction because the interference of this interaction prevented the impairment of long-term potentiation in mouse hippocampus slices. Similarly, diverse factors regulate the association between A and membrane lipid, including ions of Cu2+, Zn2+, pH, and cholesterol (Curtain et al., 2003). 4.12 Amyloid precursor protein Interestingly, A interacts with its own precursor protein, APP (Lorenzo et al., 2000). APP is a type I transmembrane protein with a large extracellular domain of N-terminus and a short
Page 28 of 68
C-terminal cytoplasmic tail. APP plays diverse developmental and functional roles including synaptic activity, response to stress, and injury repair (Panegyres, 2001). In addition, APP may function as a cell surface receptor and mediate cell adhesion and neurite outgrowth (Breen et al., 1991; Kang et al., 1987; Milward et al., 1992). In cortical neurons, its binding
ip t
affinity to the toxic fibrillar A is drastically increased compared with that to the soluble A,
cr
showing a binding affinity to fibrillary A at the nanomolar concentration range (Lorenzo et al., 2000). Furthermore, neuronal toxicity of A is mediated by the APP/A interaction,
us
because APP-null neurons exhibit reduced neurotoxicity to A. This study also showed that fibrillar A binds mainly to the cell membrane associated form of APP, but a much lower
an
interaction is detected with secreted soluble APP, which implies that a certain part of the C-
M
terminal residue or the transmembrane orientation are prerequisite for APP/A interaction.
d
5. Intracellular A-interacting proteins
Ac ce pt e
In addition to the extracellular accumulation, intracellular accumulation of A is an early event in AD pathogenesis, and the region of intraneuronal A detection is more prone to the brain region of AD pathology (hippocampus and the entorhinal cortex) in mild cognitive disorder (Gouras et al., 2000; LaFerla et al., 2007). Therefore, binding partners of intracellular A would be direct targets or mediators of intracellular A toxicity. 5.1 Endoplasmic reticulum-associated A peptide binding protein Endoplasmic reticulum-associated A peptide binding protein (ERAB) binds to A and mediates A neurotoxicity, because blocking ERAB prevents A-mediated toxicity, and its overexpression enhances toxicity (Yan et al., 1997). ERAB is an intracellular polypeptide without a signal peptide or transmembrane-spanning domain, and is considered as a hydroxysteroid dehydrogenase enzyme. Co-immunoprecipitation of ERAB and A, and overexpression of neuronal ERAB in A-treated cells suggest that intracellular binding of
Page 29 of 68
ERAB with A plays a critical role in neuronal dysfunction in AD. Additionally, extracellular A exposure upregulates ERAB, and redistributes intracellular ERAB to the plasma membrane. ERAB is an intracellular target of A, and consequently induces cellular stress and apoptosis during AD pathogenesis.
ip t
5.2 Chaperone proteins
cr
Chaperone proteins have been suggested to bind to A and modulate the metabolism, function, and toxicity of intracellular A. Using transgenic Caenorhabditis elegans, six
us
chaperone proteins were identified to bind to intracellular A, including two in the heat shock protein (Hsp) 70 family and three Hsp16 proteins (B-crystallin-related small heat shock
an
proteins), suggesting their direct and early functional contribution to age-associated
M
neurodegenerative diseases (Fonte et al., 2002). Furthermore, numerous small heat shock proteins, including Hsp20, Hsp27, HspB2, show extracellular expression, and colocalize with
d
A in amyloid plaques (Wilhelmus et al., 2006).
Ac ce pt e
5.3 X11-like, B-crystallin and lysozyme
Indirectly, intracellular protein binds to APP, and modulate the amyloidogenic process and metabolism of APP, which has a critical effect on AD pathogenesis. X11-like (X11L) is a neuronal adapter protein with a phosphotyrosin-binding (PTB) domain and two C-terminal PDZ domains, and suppresses the amyloidogenic process of mature APP by accumulating immature APP in the early secretory pathway (Saito et al., 2011). B-crystallin, the small heat-shock protein family, shows increased expression in brains from AD patients and immunoreactivity to B-crystallin in astrocyte and microglia is detected mainly in the area with senile plaques and neurofibrillary tangles (Renkawek et al., 1994). The core domain of B-crystallin binds to A, and prevents the A aggregation process, even though its structure is not altered upon A binding (Das et al., 2014). Lysozyme also binds to A and inhibits the A aggregation, competing with B-crystallin for inter-peptide interaction
Page 30 of 68
with different A binding dynamics.
6. Mitochondrial A-binding components Mitochondrial dysfunction is an early event observed during AD pathogenesis, and A-
ip t
mediated mitochondrial dysfunction has been well investigated (Canevari et al., 2004;
cr
Tillement et al., 2011). Diverse AD-related phenomena are observed in the mitochondria, including alterations in membrane permeability, dysfunction of respiratory enzymes, altered
us
mitochondrial fission/fusion balance, subsequent mitochondrial fragmentation, and abnormal localization (Casley et al., 2002; Cha et al., 2012; Moreira et al., 2002; Santos et al., 2010;
an
Wang et al., 2009b). Therefore, mitochondria are regarded as one of the main targets of A-
M
mediated toxicity, and much effort has been devoted to elucidate the relevant mitochondrial proteins and their mechanisms involved in A-induced mitochondrial toxicity (Fig. 3).
d
6.1 Cytochrome c oxidase
Ac ce pt e
Cytochrome c oxidase is a component of a respiratory chain enzyme complex localized in the mitochondrial inner membrane. This system utilizes electrons from NADH to maintain the membrane potential that is necessary for ATP generation. After passing electrons through this redox system, they are finally transferred to oxygen by cytochrome c oxidase in complex IV (Mick et al., 2011). Cytochrome c oxidase has 13 subunits, and, importantly, the aminoterminal region of cytochrome c oxidase subunit 1 binds to A 1-42, and aggregates Aβ in the brains with AD (Hernandez-Zimbron et al., 2012). This interaction results in a stable helixhelix structure, and induces deleterious effects during AD pathogenesis, including the impaired activity of respiratory chain complex IV and neuronal metabolic dysfunction (Hernandez-Zimbron et al., 2012). The direct binding of cytochrome c oxidase and A might explain the AD-related reduction in cytochrome c oxidase activity and the decrease of both oxidative stress and plaque formation in a transgenic animal model of AD with cytochrome c
Page 31 of 68
oxidase deficiency (Fukui et al., 2007; Pickrell et al., 2009). 6.2 A-binding alcohol dehydrogenase A-binding alcohol dehydrogenase (ABAD) is an enzyme composed of 261 amino acid residues localized in the mitochondrial matrix of neurons, and it directly interacts with
ip t
mitochondrial A in the mitochondria of a transgenic mouse model of AD and in patients
cr
with AD (Chen and Yan, 2007; Lustbader et al., 2004). Interaction of ABAD and A promotes neuronal oxidative stress, mitochondrial dysfunction, and cell death, leading to
us
hippocampal dysfunction and memory impairment (Lustbader et al., 2004; Pinho et al., 2014; Takuma et al., 2005). Prevention of the ABAD/A interaction ameliorates A accumulation
an
in the brain, and rescues from A-mediated apoptosis, free radical production, and
M
mitochondrial dysfunction in a mouse model of AD (Lustbader et al., 2004; Yao et al., 2011). Behavioral stress significantly aggravates AD-related pathologies, including oxidative stress,
d
mitochondrial dysfunction, and plaque formation, which are mediated by increased
Ac ce pt e
mitochondrial ABAD expression in the brain (Seo et al., 2011). This demonstrates that the expression level of ABAD is a critical factor for modulating A-mediated mitochondrial toxicity during AD pathogenesis.
6.3 Mitochondrial permeability transition pore Mitochondrial permeability transition pore (mPTP) is composed of several core proteins, including voltage-dependent anion channel (VDAC), mitochondrial benzodiazepine receptor, adenine nucleotide translocase (ANT), and cyclophilin D, which are localized in the outer and inner mitochondrial membranes (Halestrap et al., 2002). It plays a critical role in apoptotic and necrotic cell death, and has attracted much attention in AD, because A interacts with more than one component of the mPTP, and modulates pore opening. Cyclophilin D is a key factor that triggers the opening of mPTP by its translocation from the mitochondrial matrix to the mitochondrial inner membrane under oxidative and cellular stress
Page 32 of 68
(Andreeva et al., 1999; Connern and Halestrap, 1994; Henry-Mowatt et al., 2004). In studies, which performed genetic inactivation or deletion of cyclophilin D, mitochondrial permeability transition was regulated by cyclophilin D via modulating the sensitivity of mPTP to calcium overload and oxidative stress. Therefore, cyclophilin D deficits protect from
ip t
stress-induced cell death (Basso et al., 2005; Schinzel et al., 2005). During AD pathogenesis,
cr
cyclophilin D is a mitochondrial target of A mediated by their direct interaction resulting in subsequent mitochondrial dysfunction and leading to behavioral impairments, synaptic
us
dysfunction, and neuronal death. Notably, these effects can be rescued by cyclophilin D deficiency (Du et al., 2008; Du et al., 2011).
an
VDAC is another interacting partner of A in the mitochondria, localized in the
M
mitochondrial outer membrane, and it mediates the transport of metabolites in and out of the mitochondria (Colombini, 2012; Hodge and Colombini, 1997). Three VDAC isoforms have
d
been described (VDAC1, 2, and 3), and VDAC1 is the most widely expressed isoform in the
Ac ce pt e
brain (Yamamoto et al., 2006). VDAC1 expression is upregulated in the cortical tissue of patients with AD and in the cerebral cortex of APP overexpressing transgenic mice. Notably, VDAC1 interacts with A and this interaction is detected both in patients with AD and various transgenic mouse models of AD (Manczak and Reddy, 2012b). Interestingly, VDAC1 interacts not only with A, but also with phosphorylated tau, which is the second major pathological hallmark of AD. The interaction of VDAC with either A or phosphorylated tau results in abnormal operation of the mitochondrial pore, and leads to impairments in oxidative phosphorylation and mitochondrial function, possibly causing neuronal death (Manczak and Reddy, 2012b). Also, recent study has shown that A interacted with VDAC1, specifically in the N-terminal region, and induced mitochondrial dysfunction and mitochondria-mediated apoptosis, which was prevented by non-cell-penetrating VDAC1 Nterminal peptide or silencing VDAC1 expression (Smilansky et al., 2015).
Page 33 of 68
6.4 Mitochondrial enzymes Mitochondrial structural abnormalities are thought to be closely related to mitochondrial functional impairments during AD progression. Furthermore, the main cause of abnormal mitochondrial structure and morphology is the imbalance between fission and fusion (Wang
ip t
et al., 2009b; Wang et al., 2008). Diverse mitochondrial enzymes can be influenced by the
cr
direct interactions with A, which alter enzyme activities, followed by changes in mitochondrial structure and function, and finally result in mitochondrial impairment.
us
Dynamin-related protein Drp1 is one of the main GTPase proteins that maintain mitochondrial morphology and structure by regulating mitochondrial fission, together with
an
fission 1(Fis1) protein (Suen et al., 2008). Interestingly, Drp1 interacts with A in the frontal
M
cortex of patients with AD and in the cerebral cortex of transgenic mouse models of AD (Manczak et al., 2011). Drp1 expression is upregulated in AD, and this increase primarily
d
occurs in the early phase of AD. Furthermore, interaction between Drp1 and A increases
Ac ce pt e
with disease progression. This finding implies that abnormal mitochondrial dynamics are early events during AD pathogenesis (Manczak et al., 2011). In a subsequent study, it was shown that Drp1 also binds to hyperphosphorylated tau in neurons with AD, leading to increased GTPase activity, abnormal mitochondrial fragmentation, mitochondrial and synaptic dysfunction, neuronal damage, and ultimately cognitive impairment in AD (Manczak and Reddy, 2012a). Additionally, subunit of the F1F0-ATP synthase was suggested as an A-interacting mitochondrial protein (Schmidt et al., 2008). F1F0-ATP synthase, also known as complex V, is responsible for ATP production, ATP hydrolysis, and maintenance of the mitochondrial proton gradient. F1F0-ATP synthase also interacts with A at the surface of neuronal cells (Schmidt et al., 2008; von Ballmoos et al., 2009). The binding sequence of A to ATP synthase is fairly similar to that of a naturally occurring inhibitor of the ATP synthase complex in the mitochondria—inhibitor of F1, and the activity of ATP
Page 34 of 68
synthase is decreased through its interaction with A (Schmidt et al., 2008). The detailed mechanism of decreased ATP synthase activity in AD has been discovered that the direct interaction between ATP synthase subunit and A inhibited the glycosylation with O-linked -N-acetylglucosamine at Thr432 in ATP synthase, which resulted in impairments of both
ip t
ATPase activity and ATP production (Cha et al., 2015).
cr
The mitochondrial peptidasome, known as the presequence protease (PreP), is a metallopeptidase localized to the mitochondrial matrix (Alikhani et al., 2011; Falkevall et al.,
us
2006). The human PreP homologue degrades diverse forms of A, such as A1–40 and A1– 42, by direct interaction (Alikhani et al., 2011; Falkevall et al., 2006). Mitochondrial PreP
an
activity is lower in the temporal lobe of patients with AD than in controls; however, no
M
difference was observed in the cerebellum, which is spared from the accumulation and influence of A (Alikhani et al., 2011). A accumulation and increased mitochondrial
d
oxidative stress may correlate with a decreased PreP activity in AD.
Ac ce pt e
Mitochondria are one of the most vulnerable organelles affected by A. They act as repositories for diverse molecular targets for direct A interactions that might initiate and propagate AD. Therefore, it is a promising strategy for AD therapeutics to rescue mitochondrial function by modulating the expression or function of A-interacting mitochondrial proteins or by rescuing AD-related enzymatic imbalances and dysfunctions in the mitochondria.
7. A-interacting mediators of immune activation The innate immune response in AD pathogenesis is currently considered as one of the most critical issues in the field of AD research. Many studies have aimed to determine how immune cells are triggered by A itself or A-related signaling pathways, and how immune activation, including inflammatory responses, affects AD progression (Fig. 2).
Page 35 of 68
7.1 Toll-like receptors In terms of the A-induced microglial activation and inflammatory response, toll-like receptors (TLRs) may be one of the most essential mediators of A. TLRs are pattern recognition receptors expressed abundantly on innate immune cells with a prominent immune
ip t
reaction against pathogens (Akira, 2001; Gordon, 2002; Medzhitov, 2001). TLRs function as
cr
dimers, and often cooperate with co-receptors, such as cluster of differentiation (CD)14, to recognize pathogens (Baumann et al., 2010). TLR signaling is involved in A uptake and
us
clearance in the brain (Richard et al., 2008; Tahara et al., 2006). Notably, TLR2 is the primary A-binding receptor that initiates neuroinflammation (Liu et al., 2012). TLR2
an
activation induces inflammatory responses through diverse signaling pathways including
M
mitogen-activated protein 3 kinases (MAP3K), ERK, c-Jun N-terminal kinases (JNK), and p38 (Canton et al., 2013; Kariko et al., 2004; Strober et al., 2006) (Fig. 2). Furthermore,
d
TLR2 interacts with the fibrillar form of A and stimulates activation of microglia, which are
Ac ce pt e
critical components of AD pathogenesis (Jana et al., 2008). TLR2/fibrillar A42 engagement activates microglia, and consequently induces NO synthase, proinflammatory cytokines, and integrin markers, which are blocked in knockout animals or by the functional inhibition of TLR2 (Jana et al., 2008). Evidence suggests that both TLR2 and TLR4 are involved in the inflammatory response initiated by aggregated A, and specific antagonism of TLR2 and TLR4 causes ~50% and ~35% decrease in the A-induced response, respectively (Udan et al., 2008). Furthermore, fibrillar A fails to induce phagocytic responses and ROS production, or activate microglia without TLR2 or TLR4 function, as shown by the use of blocking antibodies in microglial cell lines or primary cultures from knockout mice (Reed-Geaghan et al., 2009). Accordingly, increased TLR2 and TLR4 expression was detected in the brains of APP-overexpressing transgenic mice and patients with AD, especially in a pattern associated with A plaque deposition in the entorhinal cortex (Letiembre et al., 2009; Walter et al.,
Page 36 of 68
2007). Additionally, TLR expression is closely associated with A-induced cellular toxicity, as A42 infusion greatly increases TLR2 expression in the hippocampus of wild type CD1 mice (Letiembre et al., 2009; Richard et al., 2008). Moreover, TLR2- and CD14-positive microglia are associated with A plaques in the cortex of APP overexpressing transgenic mice
ip t
(Letiembre et al., 2009; Richard et al., 2008). Similar to the central nervous system, clinical
cr
data shows increased TLR2 and TLR4 expression in peripheral blood mononuclear cells from patients with AD compared with that from controls (Zhang et al., 2012). Importantly,
us
microglial activation by TLR2 or TLR4 ligands increases the clearance of A in vitro and in vivo (Herber et al., 2007; Tahara et al., 2006), and a lipopolysaccharide (LPS)-derived
an
detoxified TLR4 agonist improves pathology in a mouse model of AD (Michaud et al., 2013).
M
Several mechanisms might explain this phenomenon, including the increased phagocytic activity of microglia by TLR activation or the TLR2-mediated upregulation of mouse G-
d
protein coupled formyl peptide receptor (mFPR2)-mediated A uptake (Chen et al., 2006).
Ac ce pt e
Therefore, ligands of TLR2 or 4 have been considered as new therapeutic candidates; however, it remains controversial whether TLR/A interaction, followed by microglial activation and induction of reactive oxygen species, is beneficial to AD pathology, because microglial activation is a complicated process, and can produce biphasic effects and diverse phenotypes depending on the environment (Mizuno, 2012; Morgan et al., 2005; Tahara et al., 2006; Walker and Lue, 2005).
7.2 Receptor for advanced glycation end products As discussed earlier, RAGE plays critical roles in A-mediated toxicity in neurons. This receptor is associated with the A-mediated activation of the immune response, and is localized at the surface of innate immunogenic cells (Fang et al., 2010; Yan et al., 1996). In addition, microglial RAGE/A interactions amplify inflammatory responses through microglial proliferation and migration (Fang et al., 2010; Yan et al., 1996). Microglial RAGE
Page 37 of 68
mediates A-induced synaptic dysfunction, including transient depression of basal synaptic functions and impairment of long term depression, which can be rescued by inhibiting microglial RAGE, but not by the suppression of RAGE in neurons (Origlia et al., 2010). Increased RAGE immunoreactivity was detected in the microglia of patients with AD,
ip t
primarily in the hippocampus (Lue et al., 2001). Additionally, RAGE/A engagement
cr
increases the expression and secretion of macrophage-colony stimulating factor (M-CSF) in both microglial cell cultures and brain-derived microglia from patients with AD, with a
us
significantly greater effect in microglia derived from the brains with AD than in those from the control brains (Lue et al., 2001). Furthermore, increased levels of M-CSF and A
an
upregulate RAGE expression, forming a positive feedback loop of microglial activation
M
induced by the RAGE/A interaction and increased M-CSF expression followed by RAGE expression, which might be a critical process during AD pathophysiology. Diverse
d
downstream signaling pathways are activated by microglial RAGE activation, which are
Ac ce pt e
shown in Figure 2 (Bianchi et al., 2007; Riehl et al., 2009). 7.3 CD36
CD36, a scavenger receptor, is expressed on monocytic lineage cells, such as microglia and macrophages. It binds to ligands with a diverse range of structures, and plays a critical role in the activation of innate immune responses. This scavenger receptor is an important mediator in the pathogenesis of AD, because lack of it abolishes A-mediated oxidative stress and cerebrovascular dysfunction in APP overexpressing mice (Park et al., 2011). Furthermore, CD36 is associated with cerebral amyloid angiopathy (CAA); it increases vascular amyloid deposition, resulting in subsequent cerebrovascular damage and dysfunction leading to cognitive impairment (Park et al., 2013). Evidence shows that A fibrils activate microglia and induce the secretion of proinflammatory cytokines by interacting with a receptor complex consisting of CD36, integrin-associated protein/CD47, and 61-integrin (Bamberger et al.,
Page 38 of 68
2003). This interaction is mediated by a tyrosine kinase-based downstream signaling cascade, and both antagonists and A peptide competitors of the CD36 receptor complex abolish the A-mediated stimulation of tyrosine kinase-based signaling and interleukin 1 production (Bamberger et al., 2003; Canton et al., 2013) (Fig. 2). The activation of tyrosine kinases Lyn
ip t
and Syk induce transient calcium release, which results in protein kinase C (PKC) and protein
cr
tyrosine kinase PYK2 (calcium sensitive tyrosine kinase) and then ERK1/ERK2 activation, leading to the generation of neurotoxic products including superoxide radicals (Combs et al.,
us
1999; McDonald et al., 1997). Furthermore, engagement of fibrillar A and this receptor complex induces a phagocytic response, which is mainly driven by 1 integrin, and is distinct
an
from the typical type I and type II phagocytic mechanisms (Koenigsknecht and Landreth,
7.4 Microglial receptors
M
2004).
d
Microglial class A scavenger receptor (SR) interacts with A fibrils via its collagen-like
Ac ce pt e
domain, and plays a critical role in microglial adhesion to fibrillary A (El Khoury et al., 1996). Furthermore, SR mediates the removal and clearance of A by its binding and uptake (Paresce et al., 1996). Additionally, A is a chemotactic agonist for immune response by binding to the FPR-Like-1 (FPRL1) receptor expressed on mononuclear phagocytes (microglial cells, monocytes, and monocytic cell lines) and inflammatory cells infiltrating the cerebral amyloid plaques in patients with AD (Le et al., 2001). FPRL1 is a seventransmembrane G protein-coupled receptor, and the association of FPRL1 and A induces proinflammatory responses through the migration and activation of monocytes in humans. While the SEC receptor mediates the internalization of A in neuronal cells, FPRL1 is involved in A internalization in macrophages, binding and internalizing A, and accumulating the fibrils form (Yazawa et al., 2001).
Page 39 of 68
8. Other amyloidogenic proteins Some amyloidogenic proteins are tightly involved in protein aggregation disorders, including transthyretin, -synuclein and A. Interestingly, they interact with each other and affect protein aggregation status, which has an impact on pathophysiology of disease progression.
ip t
Cross-seeding or cross-inhibition of aggregation is one of those outcomes for mutual
cr
interactions between amyloidogenic proteins, which is crucial to understand the neuropathological comorbidity of several neurodegenerative disorders.
us
8.1 Alpha-Synuclein
Sharing some clinical and pathophysiological features has raised the possibility of molecular
an
link between A and -synuclein, the main pathological hallmarks in AD and Parkinson’s
M
disease (PD) respectively. AD environment accelerate the formation of -synuclein fibril, proved by the effect of the CSF obtained from different neurological diseases including AD
d
(Ono et al., 2007). In doubly transgenic mice of human A peptides and -synuclein, A
Ac ce pt e
enhances -synuclein accumulation, fibril formation, and furthermore neuronal deficits (Masliah et al., 2001). In the other way, in vivo study using transgenic mice demonstrates that neurodegeneration induced by -synuclein alters ubiquitin/proteasome system, increases ApoE levels and A accumulation (Gallardo et al., 2008). A, tau and -synuclein appear to interact each other and enhance the accumulation and aggregation mutually which aggravate the cognitive dysfunction in 3XTg AD mice with mutant human -synuclein transgene (Clinton et al., 2010). Direct interaction between A and -synuclein was proved by in vitro multidimensional NMR spectroscopy study and in vivo study of brains from AD/PD patient and transgenic mice, which may be the possible pathophysiological mechanism of dementia with Lewy body disease (Mandal et al., 2006; Tsigelny et al., 2008). Cross-seeding effect has been confirmed after direct interaction between A and -synuclein (Ono et al., 2012) and this process is suspected as the molecular mechanisms contributing neuropathology. However,
Page 40 of 68
the seeming conflicting results propose that -synuclein plays a role not in cross-seeding of A plaques, but in inhibiting A plaque formation in vivo (Bachhuber et al., 2015). Significant increase of forebrain A plaque load is caused by loss of -synuclein in APP transgenic mice, which also support the idea that -synuclein is not associated with cross-
ip t
seeding of A aggregation (Kallhoff et al., 2007). In spites of these discrepancies,
cr
understanding of molecular relationship between -synuclein and A would be critical to develop effective treatment for PD and AD.
us
8.2 A40 and A42
Numerous isoforms of A peptides have properties to interact with each other. Specially,
an
A40 and A42 are in the center of interest because their interacting patterns and aggregating
M
status are tightly related to pathogenesis of AD. A40 interacts with A42 and affects propensity of aggregation, inhibiting A42 oligomerization, aggregation and amyloid
d
deposition (Kim et al., 2007; Murray et al., 2009; Yan and Wang, 2007). A40 interacts to
Ac ce pt e
A42 in concentration and ratio-dependent manner, changes the solubility, stability and morphological characteristics of A42 aggregates and finally inhibits the further maturation into fibrillization according to the ratio of A40 to A42 (Jan et al., 2008). Equilibrium point of the amyloid peptides has been suggested to be dependent upon the A40/A42 ratio and implicated in pathogenesis of AD. Besides affecting A42 aggregation pattern, A40-bound A42 oligomers are less toxic than A42 alone oligomers, reducing the toxicity on synapse including synaptic vesicle recycling and synaptophysin level (Bate and Williams, 2010). The possible mechanism for this less toxicity is the alleviation of cytoplasmic phospholipase A2 activation induced by A42 in synapse (Bate and Williams, 2010). BRI2 protein is type2 transmembrane protein with 266 amino acids and the two mutations in the ITM2b gene encoding BRI2 is responsible for familial British and Danish dementias which are neurodegenerative dementia characterized by neuronal loss, amyloid deposits, neurofibrillary
Page 41 of 68
tangles and cerebral amyloid angiopathy (Ghiso et al., 2006). Similar to the beneficial effect of A40, wild-type human BRI2 expression is reported to decrease A deposit in AD mouse model and bri23 released BRI2 prevents A aggregation in vitro which may mediate the antiamyloidogenic effect in vivo (Kim et al., 2008).
ip t
8.3 Transthyretin
cr
Transthyretin modulates A deposition by direct interaction and co-localizes in plaques with A (Buxbaum et al., 2008). Overexpression of human transthyretin was ameliorative while
us
the removals of transthyretin expression in diverse transgenic animal models aggravate the neuropathological phenotype caused by A, which suggest that transthyretin is protective by
an
binding to A aggregates in intracellular and extracellular compartment (Buxbaum et al.,
M
2008; Choi et al., 2007). However, in spite of beneficial effect of transthyretin to A pathology, transthyretin has no effect on reduction of A deposition, rather accelerate total
Ac ce pt e
d
and vascular A deposition in the mouse model of AD (Wati et al., 2009).
9. Conclusion
A-interacting molecules influence the etiology of AD, and may become useful indicative biomarkers or therapeutic targets following alterations in their expression levels in the brain or periphery. To date, multiple clinical trials targeting A resulted in disappointing failures. Therefore, researchers have realized that A is likely not the sole cause of AD, and have sought alternative therapeutic approaches. A-interacting molecules have attracted much attention based on their association with the predominant etiological factor A. Beneficial effects of the modulation of A-interacting partners during AD pathogenesis and disease progression have further expanded the fields of clinical application for possible AD therapeutics (Table 1). Specially, peripheral blood is a dynamic environment reflecting diverse changes in molecular and cellular functions in different regions of the body. Plasma
Page 42 of 68
levels of A-interacting proteins change during AD pathogenesis, and these alterations dependent on disease progression may provide critical information as diagnostic and surrogate biomarker. Also, multiple forms of A elicit diverse effects on intracellular organelles, neurons and synapses through binding to cellular, membrane and other effector
ip t
proteins. Thus, perturbation of these events may be the primary step to prevent the initiation
cr
or progression of AD and further utilized in therapeutic strategy. Investigation of specific A binding sites in A-interacting proteins would be helpful to inhibit or enhance interactions,
us
depending on the beneficial or deleterious effects resulted from these interactions. Further binding affinity studies for molecular structure modification may provide a better
an
understanding and discovery of effective binding competitors might open promising avenues
M
for the future development of AD therapeutic drugs modified from specific A-interacting
d
molecules.
This
Ac ce pt e
Acknowledgement work
was
supported
by
grants
from
NRF
(2015R1A2A1A05001794,
2014M3C7A1046047, 2015M3C7A1028790 and MRC (2012R1A5A2A44671346)) for I.MJ.
Page 43 of 68
References
Ac ce pt e
d
M
an
us
cr
ip t
Adlard, P. A., Parncutt, J. M., Finkelstein, D. I. and Bush, A. I. (2010) Cognitive loss in zinc transporter-3 knock-out mice: a phenocopy for the synaptic and memory deficits of Alzheimer's disease? The Journal of neuroscience : the official journal of the Society for Neuroscience 30, 1631-1636. Aicardi, G. (2013) New hope from an old drug: fighting Alzheimer's disease with the cancer drug bexarotene (targretin)? Rejuvenation research 16, 524-528. Akira, S. (2001) Toll-like receptors and innate immunity. Advances in immunology 78, 1-56. Aleshkov, S., Abraham, C. R. and Zannis, V. I. (1997) Interaction of nascent ApoE2, ApoE3, and ApoE4 isoforms expressed in mammalian cells with amyloid peptide beta (1-40). Relevance to Alzheimer's disease. Biochemistry 36, 10571-10580. Alier, K., Ma, L., Yang, J., Westaway, D. and Jhamandas, J. H. (2011) Abeta inhibition of ionic conductance in mouse basal forebrain neurons is dependent upon the cellular prion protein PrPC. The Journal of neuroscience : the official journal of the Society for Neuroscience 31, 16292-16297. Alikhani, N., Guo, L., Yan, S., Du, H., Pinho, C. M., Chen, J. X., Glaser, E. and Yan, S. S. (2011) Decreased proteolytic activity of the mitochondrial amyloid-beta degrading enzyme, PreP peptidasome, in Alzheimer's disease brain mitochondria. Journal of Alzheimer's disease : JAD 27, 75-87. Andreeva, L., Heads, R. and Green, C. J. (1999) Cyclophilins and their possible role in the stress response. International journal of experimental pathology 80, 305-315. Arancio, O., Zhang, H. P., Chen, X., Lin, C., Trinchese, F., Puzzo, D., Liu, S., Hegde, A., Yan, S. F., Stern, A., Luddy, J. S., Lue, L. F., Walker, D. G., Roher, A., Buttini, M., Mucke, L., Li, W., Schmidt, A. M., Kindy, M., Hyslop, P. A., Stern, D. M. and Du Yan, S. S. (2004) RAGE potentiates Abeta-induced perturbation of neuronal function in transgenic mice. The EMBO journal 23, 4096-4105. Aronow, B. J., Lund, S. D., Brown, T. L., Harmony, J. A. and Witte, D. P. (1993) Apolipoprotein J expression at fluid-tissue interfaces: potential role in barrier cytoprotection. Proceedings of the National Academy of Sciences of the United States of America 90, 725-729. Atwal, J. K., Pinkston-Gosse, J., Syken, J., Stawicki, S., Wu, Y., Shatz, C. and Tessier-Lavigne, M. (2008) PirB is a functional receptor for myelin inhibitors of axonal regeneration. Science 322, 967-970. Atwood, C. S., Moir, R. D., Huang, X., Scarpa, R. C., Bacarra, N. M., Romano, D. M., Hartshorn, M. A., Tanzi, R. E. and Bush, A. I. (1998) Dramatic aggregation of Alzheimer abeta by Cu(II) is induced by conditions representing physiological acidosis. The Journal of biological chemistry 273, 12817-12826. Bachhuber, T., Katzmarski, N., McCarter, J. F., Loreth, D., Tahirovic, S., Kamp, F., Abou-Ajram, C., Nuscher, B., Serrano-Pozo, A., Muller, A., Prinz, M., Steiner, H., Hyman, B. T., Haass, C. and Meyer-Luehmann, M. (2015) Inhibition of amyloid-beta plaque formation by alpha-synuclein. Nature medicine 21, 802807. Bales, K. R., Verina, T., Dodel, R. C., Du, Y., Altstiel, L., Bender, M., Hyslop, P., Johnstone, E. M., Little, S. P., Cummins, D. J., Piccardo, P., Ghetti, B. and Paul, S. M. (1997) Lack of apolipoprotein E dramatically reduces amyloid beta-peptide deposition. Nature genetics 17, 263-264. Bamberger, M. E., Harris, M. E., McDonald, D. R., Husemann, J. and Landreth, G. E. (2003) A cell surface receptor complex for fibrillar beta-amyloid mediates microglial activation. The Journal of neuroscience : the official journal of the Society for Neuroscience 23, 2665-2674. Banks, W. A., Maness, L. M., Banks, M. F. and Kastin, A. J. (1996) Aluminum-sensitive degradation of amyloid beta-protein 1-40 by murine and human intracellular enzymes. Neurotoxicology and teratology 18, 671-677. Basak, J. M., Verghese, P. B., Yoon, H., Kim, J. and Holtzman, D. M. (2012) Low-density lipoprotein receptor represents an apolipoprotein E-independent pathway of Abeta uptake and degradation by astrocytes. The Journal of biological chemistry 287, 13959-13971. Basso, E., Fante, L., Fowlkes, J., Petronilli, V., Forte, M. A. and Bernardi, P. (2005) Properties of the permeability transition pore in mitochondria devoid of Cyclophilin D. The Journal of biological chemistry 280, 18558-18561. Bate, C. and Williams, A. (2010) Amyloid-beta(1-40) inhibits amyloid-beta(1-42) induced activation of cytoplasmic phospholipase A2 and synapse degeneration. Journal of Alzheimer's disease : JAD 21, 985-993. Bate, C. and Williams, A. (2011) Amyloid-beta-induced synapse damage is mediated via cross-linkage of cellular prion proteins. The Journal of biological chemistry 286, 37955-37963. Baumann, C. L., Aspalter, I. M., Sharif, O., Pichlmair, A., Bluml, S., Grebien, F., Bruckner, M., Pasierbek, P., Aumayr, K., Planyavsky, M., Bennett, K. L., Colinge, J., Knapp, S. and Superti-Furga, G. (2010) CD14 is a coreceptor of Toll-like receptors 7 and 9. The Journal of experimental medicine 207, 2689-2701. Bayer, T. A., Schafer, S., Simons, A., Kemmling, A., Kamer, T., Tepest, R., Eckert, A., Schussel, K., Eikenberg,
Page 44 of 68
Ac ce pt e
d
M
an
us
cr
ip t
O., Sturchler-Pierrat, C., Abramowski, D., Staufenbiel, M. and Multhaup, G. (2003) Dietary Cu stabilizes brain superoxide dismutase 1 activity and reduces amyloid Abeta production in APP23 transgenic mice. Proceedings of the National Academy of Sciences of the United States of America 100, 14187-14192. Benilova, I. and De Strooper, B. (2013) Neuroscience. Promiscuous Alzheimer's amyloid: yet another partner. Science 341, 1354-1355. Bi, X., Gall, C. M., Zhou, J. and Lynch, G. (2002) Uptake and pathogenic effects of amyloid beta peptide 1-42 are enhanced by integrin antagonists and blocked by NMDA receptor antagonists. Neuroscience 112, 827-840. Bianchi, R., Adami, C., Giambanco, I. and Donato, R. (2007) S100B binding to RAGE in microglia stimulates COX-2 expression. Journal of leukocyte biology 81, 108-118. Bien-Ly, N., Gillespie, A. K., Walker, D., Yoon, S. Y. and Huang, Y. (2012) Reducing human apolipoprotein E levels attenuates age-dependent Abeta accumulation in mutant human amyloid precursor protein transgenic mice. The Journal of neuroscience : the official journal of the Society for Neuroscience 32, 4803-4811. Biere, A. L., Ostaszewski, B., Stimson, E. R., Hyman, B. T., Maggio, J. E. and Selkoe, D. J. (1996) Amyloid beta-peptide is transported on lipoproteins and albumin in human plasma. The Journal of biological chemistry 271, 32916-32922. Blacker, D., Wilcox, M. A., Laird, N. M., Rodes, L., Horvath, S. M., Go, R. C., Perry, R., Watson, B., Jr., Bassett, S. S., McInnis, M. G., Albert, M. S., Hyman, B. T. and Tanzi, R. E. (1998) Alpha-2 macroglobulin is genetically associated with Alzheimer disease. Nature genetics 19, 357-360. Boada, M., Ortiz, P., Anaya, F., Hernandez, I., Munoz, J., Nunez, L., Olazaran, J., Roca, I., Cuberas, G., Tarraga, L., Buendia, M., Pla, R. P., Ferrer, I. and Paez, A. (2009) Amyloid-targeted therapeutics in Alzheimer's disease: use of human albumin in plasma exchange as a novel approach for Abeta mobilization. Drug news & perspectives 22, 325-339. Bohrmann, B., Tjernberg, L., Kuner, P., Poli, S., Levet-Trafit, B., Naslund, J., Richards, G., Huber, W., Dobeli, H. and Nordstedt, C. (1999) Endogenous proteins controlling amyloid beta-peptide polymerization. Possible implications for beta-amyloid formation in the central nervous system and in peripheral tissues. The Journal of biological chemistry 274, 15990-15995. Boland, K., Behrens, M., Choi, D., Manias, K. and Perlmutter, D. H. (1996) The serpin-enzyme complex receptor recognizes soluble, nontoxic amyloid-beta peptide but not aggregated, cytotoxic amyloid-beta peptide. The Journal of biological chemistry 271, 18032-18044. Boland, K., Manias, K. and Perlmutter, D. H. (1995) Specificity in recognition of amyloid-beta peptide by the serpin-enzyme complex receptor in hepatoma cells and neuronal cells. The Journal of biological chemistry 270, 28022-28028. Bousejra-ElGarah, F., Bijani, C., Coppel, Y., Faller, P. and Hureau, C. (2011) Iron(II) binding to amyloid-beta, the Alzheimer's peptide. Inorganic chemistry 50, 9024-9030. Breen, K. C., Bruce, M. and Anderton, B. H. (1991) Beta amyloid precursor protein mediates neuronal cell-cell and cell-surface adhesion. Journal of neuroscience research 28, 90-100. Breese, C. R., Adams, C., Logel, J., Drebing, C., Rollins, Y., Barnhart, M., Sullivan, B., Demasters, B. K., Freedman, R. and Leonard, S. (1997) Comparison of the regional expression of nicotinic acetylcholine receptor alpha7 mRNA and [125I]-alpha-bungarotoxin binding in human postmortem brain. The Journal of comparative neurology 387, 385-398. Brewer, G. J., Kanzer, S. H., Zimmerman, E. A., Celmins, D. F., Heckman, S. M. and Dick, R. (2010) Copper and ceruloplasmin abnormalities in Alzheimer's disease. American journal of Alzheimer's disease and other dementias 25, 490-497. Bu, G., Maksymovitch, E. A., Nerbonne, J. M. and Schwartz, A. L. (1994) Expression and function of the low density lipoprotein receptor-related protein (LRP) in mammalian central neurons. The Journal of biological chemistry 269, 18521-18528. Burstein, A. H., Grimes, I., Galasko, D. R., Aisen, P. S., Sabbagh, M. and Mjalli, A. M. (2014) Effect of TTP488 in patients with mild to moderate Alzheimer's disease. BMC neurology 14, 12. Bush, A. I. (2013) The metal theory of Alzheimer's disease. Journal of Alzheimer's disease : JAD 33 Suppl 1, S277-281. Buttini, M., Yu, G. Q., Shockley, K., Huang, Y., Jones, B., Masliah, E., Mallory, M., Yeo, T., Longo, F. M. and Mucke, L. (2002) Modulation of Alzheimer-like synaptic and cholinergic deficits in transgenic mice by human apolipoprotein E depends on isoform, aging, and overexpression of amyloid beta peptides but not on plaque formation. The Journal of neuroscience : the official journal of the Society for Neuroscience 22, 10539-10548. Buxbaum, J. N., Ye, Z., Reixach, N., Friske, L., Levy, C., Das, P., Golde, T., Masliah, E., Roberts, A. R. and
Page 45 of 68
Ac ce pt e
d
M
an
us
cr
ip t
Bartfai, T. (2008) Transthyretin protects Alzheimer's mice from the behavioral and biochemical effects of Abeta toxicity. Proceedings of the National Academy of Sciences of the United States of America 105, 2681-2686. Calero, M., Rostagno, A., Matsubara, E., Zlokovic, B., Frangione, B. and Ghiso, J. (2000) Apolipoprotein J (clusterin) and Alzheimer's disease. Microscopy research and technique 50, 305-315. Campbell, A., Kumar, A., La Rosa, F. G., Prasad, K. N. and Bondy, S. C. (2000) Aluminum increases levels of beta-amyloid and ubiquitin in neuroblastoma but not in glioma cells. Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine 223, 397-402. Canevari, L., Abramov, A. Y. and Duchen, M. R. (2004) Toxicity of amyloid beta peptide: tales of calcium, mitochondria, and oxidative stress. Neurochemical research 29, 637-650. Canton, J., Neculai, D. and Grinstein, S. (2013) Scavenger receptors in homeostasis and immunity. Nature reviews. Immunology 13, 621-634. Carter, D. C. and Ho, J. X. (1994) Structure of serum albumin. Advances in protein chemistry 45, 153-203. Casley, C. S., Canevari, L., Land, J. M., Clark, J. B. and Sharpe, M. A. (2002) Beta-amyloid inhibits integrated mitochondrial respiration and key enzyme activities. Journal of neurochemistry 80, 91-100. Castano, E. M., Prelli, F., Wisniewski, T., Golabek, A., Kumar, R. A., Soto, C. and Frangione, B. (1995) Fibrillogenesis in Alzheimer's disease of amyloid beta peptides and apolipoprotein E. The Biochemical journal 306 ( Pt 2), 599-604. Castano, E. M., Roher, A. E., Esh, C. L., Kokjohn, T. A. and Beach, T. (2006) Comparative proteomics of cerebrospinal fluid in neuropathologically-confirmed Alzheimer's disease and non-demented elderly subjects. Neurological research 28, 155-163. Cedazo-Minguez, A., Wiehager, B., Winblad, B., Huttinger, M. and Cowburn, R. F. (2001) Effects of apolipoprotein E (apoE) isoforms, beta-amyloid (Abeta) and apoE/Abeta complexes on protein kinase C-alpha (PKC-alpha) translocation and amyloid precursor protein (APP) processing in human SHSY5Y neuroblastoma cells and fibroblasts. Neurochemistry international 38, 615-625. Cha, M. Y., Cho, H. J., Kim, C., Jung, Y. O., Kang, M. J., Murray, M. E., Hong, H. S., Choi, Y. J., Choi, H., Kim, D. K., Choi, H., Kim, J., Dickson, D. W., Song, H. K., Cho, J. W., Yi, E. C., Kim, J., Jin, S. M. and Mook-Jung, I. (2015) Mitochondrial ATP synthase activity is impaired by suppressed O-GlcNAcylation in Alzheimer's disease. Human molecular genetics 24, 6492-6504. Cha, M. Y., Han, S. H., Son, S. M., Hong, H. S., Choi, Y. J., Byun, J. and Mook-Jung, I. (2012) Mitochondriaspecific accumulation of amyloid beta induces mitochondrial dysfunction leading to apoptotic cell death. PloS one 7, e34929. Chappell, D. A., Fry, G. L., Waknitz, M. A., Iverius, P. H., Williams, S. E. and Strickland, D. K. (1992) The low density lipoprotein receptor-related protein/alpha 2-macroglobulin receptor binds and mediates catabolism of bovine milk lipoprotein lipase. The Journal of biological chemistry 267, 25764-25767. Chen, J. X. and Yan, S. D. (2007) Amyloid-beta-induced mitochondrial dysfunction. Journal of Alzheimer's disease : JAD 12, 177-184. Chen, K., Iribarren, P., Hu, J., Chen, J., Gong, W., Cho, E. H., Lockett, S., Dunlop, N. M. and Wang, J. M. (2006) Activation of Toll-like receptor 2 on microglia promotes cell uptake of Alzheimer disease-associated amyloid beta peptide. The Journal of biological chemistry 281, 3651-3659. Cherny, R. A., Atwood, C. S., Xilinas, M. E., Gray, D. N., Jones, W. D., McLean, C. A., Barnham, K. J., Volitakis, I., Fraser, F. W., Kim, Y., Huang, X., Goldstein, L. E., Moir, R. D., Lim, J. T., Beyreuther, K., Zheng, H., Tanzi, R. E., Masters, C. L. and Bush, A. I. (2001) Treatment with a copper-zinc chelator markedly and rapidly inhibits beta-amyloid accumulation in Alzheimer's disease transgenic mice. Neuron 30, 665-676. Cho, H. J., Son, S. M., Jin, S. M., Hong, H. S., Shin, D. H., Kim, S. J., Huh, K. and Mook-Jung, I. (2009) RAGE regulates BACE1 and Abeta generation via NFAT1 activation in Alzheimer's disease animal model. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 23, 2639-2649. Choi, B. R., Cho, W. H., Kim, J., Lee, H. J., Chung, C., Jeon, W. K. and Han, J. S. (2014) Increased expression of the receptor for advanced glycation end products in neurons and astrocytes in a triple transgenic mouse model of Alzheimer's disease. Experimental & molecular medicine 46, e75. Choi, S. H., Leight, S. N., Lee, V. M., Li, T., Wong, P. C., Johnson, J. A., Saraiva, M. J. and Sisodia, S. S. (2007) Accelerated Abeta deposition in APPswe/PS1deltaE9 mice with hemizygous deletions of TTR (transthyretin). The Journal of neuroscience : the official journal of the Society for Neuroscience 27, 7006-7010. Chung, E., Ji, Y., Sun, Y., Kascsak, R. J., Kascsak, R. B., Mehta, P. D., Strittmatter, S. M. and Wisniewski, T. (2010) Anti-PrPC monoclonal antibody infusion as a novel treatment for cognitive deficits in an Alzheimer's disease model mouse. BMC neuroscience 11, 130.
Page 46 of 68
Ac ce pt e
d
M
an
us
cr
ip t
Cisse, M., Halabisky, B., Harris, J., Devidze, N., Dubal, D. B., Sun, B., Orr, A., Lotz, G., Kim, D. H., Hamto, P., Ho, K., Yu, G. Q. and Mucke, L. (2011) Reversing EphB2 depletion rescues cognitive functions in Alzheimer model. Nature 469, 47-52. Clauberg, M. and Joshi, J. G. (1993) Regulation of serine protease activity by aluminum: implications for Alzheimer disease. Proceedings of the National Academy of Sciences of the United States of America 90, 1009-1012. Clinton, L. K., Blurton-Jones, M., Myczek, K., Trojanowski, J. Q. and LaFerla, F. M. (2010) Synergistic Interactions between Abeta, tau, and alpha-synuclein: acceleration of neuropathology and cognitive decline. The Journal of neuroscience : the official journal of the Society for Neuroscience 30, 72817289. Colombini, M. (2012) VDAC structure, selectivity, and dynamics. Biochimica et biophysica acta 1818, 14571465. Combs, C. K., Johnson, D. E., Cannady, S. B., Lehman, T. M. and Landreth, G. E. (1999) Identification of microglial signal transduction pathways mediating a neurotoxic response to amyloidogenic fragments of beta-amyloid and prion proteins. The Journal of neuroscience : the official journal of the Society for Neuroscience 19, 928-939. Connern, C. P. and Halestrap, A. P. (1994) Recruitment of mitochondrial cyclophilin to the mitochondrial inner membrane under conditions of oxidative stress that enhance the opening of a calcium-sensitive nonspecific channel. The Biochemical journal 302 ( Pt 2), 321-324. Costa, M., Ortiz, A. M. and Jorquera, J. I. (2012) Therapeutic albumin binding to remove amyloid-beta. Journal of Alzheimer's disease : JAD 29, 159-170. Costa, R., Ferreira-da-Silva, F., Saraiva, M. J. and Cardoso, I. (2008) Transthyretin protects against A-beta peptide toxicity by proteolytic cleavage of the peptide: a mechanism sensitive to the Kunitz protease inhibitor. PloS one 3, e2899. Cramer, P. E., Cirrito, J. R., Wesson, D. W., Lee, C. Y., Karlo, J. C., Zinn, A. E., Casali, B. T., Restivo, J. L., Goebel, W. D., James, M. J., Brunden, K. R., Wilson, D. A. and Landreth, G. E. (2012) ApoE-directed therapeutics rapidly clear beta-amyloid and reverse deficits in AD mouse models. Science 335, 15031506. Crouch, P. J. and Barnham, K. J. (2012) Therapeutic redistribution of metal ions to treat Alzheimer's disease. Accounts of chemical research 45, 1604-1611. Cuajungco, M. P. and Faget, K. Y. (2003) Zinc takes the center stage: its paradoxical role in Alzheimer's disease. Brain research. Brain research reviews 41, 44-56. Curtain, C. C., Ali, F. E., Smith, D. G., Bush, A. I., Masters, C. L. and Barnham, K. J. (2003) Metal ions, pH, and cholesterol regulate the interactions of Alzheimer's disease amyloid-beta peptide with membrane lipid. The Journal of biological chemistry 278, 2977-2982. Dai, W., Yang, J., Chen, T. and Yang, Z. (2014) Protective Effects of Bexarotene against Amyloid-beta-Induced Dysfunction in Hippocampal Neurons through the Insulin Signaling Pathway. Neuro-degenerative diseases. Danscher, G., Jensen, K. B., Frederickson, C. J., Kemp, K., Andreasen, A., Juhl, S., Stoltenberg, M. and Ravid, R. (1997) Increased amount of zinc in the hippocampus and amygdala of Alzheimer's diseased brains: a proton-induced X-ray emission spectroscopic analysis of cryostat sections from autopsy material. Journal of neuroscience methods 76, 53-59. Danysz, W. and Parsons, C. G. (2012) Alzheimer's disease, beta-amyloid, glutamate, NMDA receptors and memantine--searching for the connections. British journal of pharmacology 167, 324-352. Das, P., Kang, S. G., Temple, S. and Belfort, G. (2014) Interaction of amyloid inhibitor proteins with amyloid beta peptides: insight from molecular dynamics simulations. PloS one 9, e113041. de Arriba, S. G., Loske, C., Meiners, I., Fleischer, G., Lobisch, M., Wessel, K., Tritschler, H., Schinzel, R. and Munch, G. (2003) Advanced glycation endproducts induce changes in glucose consumption, lactate production, and ATP levels in SH-SY5Y neuroblastoma cells by a redox-sensitive mechanism. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 23, 1307-1313. de Silva, H. V., Harmony, J. A., Stuart, W. D., Gil, C. M. and Robbins, J. (1990) Apolipoprotein J: structure and tissue distribution. Biochemistry 29, 5380-5389. Deane, R., Du Yan, S., Submamaryan, R. K., LaRue, B., Jovanovic, S., Hogg, E., Welch, D., Manness, L., Lin, C., Yu, J., Zhu, H., Ghiso, J., Frangione, B., Stern, A., Schmidt, A. M., Armstrong, D. L., Arnold, B., Liliensiek, B., Nawroth, P., Hofman, F., Kindy, M., Stern, D. and Zlokovic, B. (2003) RAGE mediates amyloid-beta peptide transport across the blood-brain barrier and accumulation in brain. Nature medicine 9, 907-913. Deane, R., Singh, I., Sagare, A. P., Bell, R. D., Ross, N. T., LaRue, B., Love, R., Perry, S., Paquette, N., Deane,
Page 47 of 68
Ac ce pt e
d
M
an
us
cr
ip t
R. J., Thiyagarajan, M., Zarcone, T., Fritz, G., Friedman, A. E., Miller, B. L. and Zlokovic, B. V. (2012) A multimodal RAGE-specific inhibitor reduces amyloid beta-mediated brain disorder in a mouse model of Alzheimer disease. The Journal of clinical investigation 122, 1377-1392. Deane, R., Wu, Z., Sagare, A., Davis, J., Du Yan, S., Hamm, K., Xu, F., Parisi, M., LaRue, B., Hu, H. W., Spijkers, P., Guo, H., Song, X., Lenting, P. J., Van Nostrand, W. E. and Zlokovic, B. V. (2004) LRP/amyloid beta-peptide interaction mediates differential brain efflux of Abeta isoforms. Neuron 43, 333-344. Deane, R. and Zlokovic, B. V. (2007) Role of the blood-brain barrier in the pathogenesis of Alzheimer's disease. Current Alzheimer research 4, 191-197. Deibel, M. A., Ehmann, W. D. and Markesbery, W. R. (1996) Copper, iron, and zinc imbalances in severely degenerated brain regions in Alzheimer's disease: possible relation to oxidative stress. Journal of the neurological sciences 143, 137-142. Diarra, A., Geetha, T., Potter, P. and Babu, J. R. (2009) Signaling of the neurotrophin receptor p75 in relation to Alzheimer's disease. Biochemical and biophysical research communications 390, 352-356. Dinamarca, M. C., Rios, J. A. and Inestrosa, N. C. (2012) Postsynaptic Receptors for Amyloid-beta Oligomers as Mediators of Neuronal Damage in Alzheimer's Disease. Frontiers in physiology 3, 464. Donahue, J. E., Flaherty, S. L., Johanson, C. E., Duncan, J. A., 3rd, Silverberg, G. D., Miller, M. C., Tavares, R., Yang, W., Wu, Q., Sabo, E., Hovanesian, V. and Stopa, E. G. (2006) RAGE, LRP-1, and amyloid-beta protein in Alzheimer's disease. Acta neuropathologica 112, 405-415. Dougherty, J. J., Wu, J. and Nichols, R. A. (2003) Beta-amyloid regulation of presynaptic nicotinic receptors in rat hippocampus and neocortex. The Journal of neuroscience : the official journal of the Society for Neuroscience 23, 6740-6747. Du, H., Guo, L., Fang, F., Chen, D., Sosunov, A. A., McKhann, G. M., Yan, Y., Wang, C., Zhang, H., Molkentin, J. D., Gunn-Moore, F. J., Vonsattel, J. P., Arancio, O., Chen, J. X. and Yan, S. D. (2008) Cyclophilin D deficiency attenuates mitochondrial and neuronal perturbation and ameliorates learning and memory in Alzheimer's disease. Nature medicine 14, 1097-1105. Du, H., Guo, L., Zhang, W., Rydzewska, M. and Yan, S. (2011) Cyclophilin D deficiency improves mitochondrial function and learning/memory in aging Alzheimer disease mouse model. Neurobiology of aging 32, 398-406. Du, J., Cho, P. Y., Yang, D. T. and Murphy, R. M. (2012) Identification of beta-amyloid-binding sites on transthyretin. Protein engineering, design & selection : PEDS 25, 337-345. Du, Y., Ni, B., Glinn, M., Dodel, R. C., Bales, K. R., Zhang, Z., Hyslop, P. A. and Paul, S. M. (1997) alpha2Macroglobulin as a beta-amyloid peptide-binding plasma protein. Journal of neurochemistry 69, 299305. Duce, J. A., Tsatsanis, A., Cater, M. A., James, S. A., Robb, E., Wikhe, K., Leong, S. L., Perez, K., Johanssen, T., Greenough, M. A., Cho, H. H., Galatis, D., Moir, R. D., Masters, C. L., McLean, C., Tanzi, R. E., Cappai, R., Barnham, K. J., Ciccotosto, G. D., Rogers, J. T. and Bush, A. I. (2010) Iron-export ferroxidase activity of beta-amyloid precursor protein is inhibited by zinc in Alzheimer's disease. Cell 142, 857-867. Duguid, J. R., Bohmont, C. W., Liu, N. G. and Tourtellotte, W. W. (1989) Changes in brain gene expression shared by scrapie and Alzheimer disease. Proceedings of the National Academy of Sciences of the United States of America 86, 7260-7264. El Khoury, J., Hickman, S. E., Thomas, C. A., Cao, L., Silverstein, S. C. and Loike, J. D. (1996) Scavenger receptor-mediated adhesion of microglia to beta-amyloid fibrils. Nature 382, 716-719. Eriksson, S., Janciauskiene, S. and Lannfelt, L. (1995) Alpha 1-antichymotrypsin regulates Alzheimer betaamyloid peptide fibril formation. Proceedings of the National Academy of Sciences of the United States of America 92, 2313-2317. Exley, C. (2005) The aluminium-amyloid cascade hypothesis and Alzheimer's disease. Sub-cellular biochemistry 38, 225-234. Exley, C. (2006) Aluminium and iron, but neither copper nor zinc, are key to the precipitation of beta-sheets of Abeta_{42} in senile plaque cores in Alzheimer's disease. Journal of Alzheimer's disease : JAD 10, 173-177. Exley, C. and Korchazhkina, O. V. (2001) Promotion of formation of amyloid fibrils by aluminium adenosine triphosphate (AlATP). Journal of inorganic biochemistry 84, 215-224. Exley, C., Price, N. C., Kelly, S. M. and Birchall, J. D. (1993) An interaction of beta-amyloid with aluminium in vitro. FEBS letters 324, 293-295. Fagan, A. M., Watson, M., Parsadanian, M., Bales, K. R., Paul, S. M. and Holtzman, D. M. (2002) Human and murine ApoE markedly alters A beta metabolism before and after plaque formation in a mouse model of Alzheimer's disease. Neurobiology of disease 9, 305-318.
Page 48 of 68
Ac ce pt e
d
M
an
us
cr
ip t
Falkevall, A., Alikhani, N., Bhushan, S., Pavlov, P. F., Busch, K., Johnson, K. A., Eneqvist, T., Tjernberg, L., Ankarcrona, M. and Glaser, E. (2006) Degradation of the amyloid beta-protein by the novel mitochondrial peptidasome, PreP. The Journal of biological chemistry 281, 29096-29104. Faller, P. (2009) Copper and zinc binding to amyloid-beta: coordination, dynamics, aggregation, reactivity and metal-ion transfer. Chembiochem : a European journal of chemical biology 10, 2837-2845. Fang, F., Lue, L. F., Yan, S., Xu, H., Luddy, J. S., Chen, D., Walker, D. G., Stern, D. M., Yan, S., Schmidt, A. M., Chen, J. X. and Yan, S. S. (2010) RAGE-dependent signaling in microglia contributes to neuroinflammation, Abeta accumulation, and impaired learning/memory in a mouse model of Alzheimer's disease. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 24, 1043-1055. Faux, N. G., Ritchie, C. W., Gunn, A., Rembach, A., Tsatsanis, A., Bedo, J., Harrison, J., Lannfelt, L., Blennow, K., Zetterberg, H., Ingelsson, M., Masters, C. L., Tanzi, R. E., Cummings, J. L., Herd, C. M. and Bush, A. I. (2010) PBT2 rapidly improves cognition in Alzheimer's Disease: additional phase II analyses. Journal of Alzheimer's disease : JAD 20, 509-516. Fonte, V., Kapulkin, W. J., Taft, A., Fluet, A., Friedman, D. and Link, C. D. (2002) Interaction of intracellular beta amyloid peptide with chaperone proteins. Proceedings of the National Academy of Sciences of the United States of America 99, 9439-9444. Freir, D. B., Nicoll, A. J., Klyubin, I., Panico, S., Mc Donald, J. M., Risse, E., Asante, E. A., Farrow, M. A., Sessions, R. B., Saibil, H. R., Clarke, A. R., Rowan, M. J., Walsh, D. M. and Collinge, J. (2011) Interaction between prion protein and toxic amyloid beta assemblies can be therapeutically targeted at multiple sites. Nature communications 2, 336. Fuentealba, R. A., Liu, Q., Zhang, J., Kanekiyo, T., Hu, X., Lee, J. M., LaDu, M. J. and Bu, G. (2010) Lowdensity lipoprotein receptor-related protein 1 (LRP1) mediates neuronal Abeta42 uptake and lysosomal trafficking. PloS one 5, e11884. Fukui, H., Diaz, F., Garcia, S. and Moraes, C. T. (2007) Cytochrome c oxidase deficiency in neurons decreases both oxidative stress and amyloid formation in a mouse model of Alzheimer's disease. Proceedings of the National Academy of Sciences of the United States of America 104, 14163-14168. Galasko, D., Bell, J., Mancuso, J. Y., Kupiec, J. W., Sabbagh, M. N., van Dyck, C., Thomas, R. G., Aisen, P. S. and Alzheimer's Disease Cooperative, S. (2014) Clinical trial of an inhibitor of RAGE-Abeta interactions in Alzheimer disease. Neurology 82, 1536-1542. Gallardo, G., Schluter, O. M. and Sudhof, T. C. (2008) A molecular pathway of neurodegeneration linking alpha-synuclein to ApoE and Abeta peptides. Nature neuroscience 11, 301-308. Gault, L. M., Ritchie, C. W., Robieson, W. Z., Pritchett, Y., Othman, A. A. and Lenz, R. A. (2015) A phase 2 randomized, controlled trial of the 7 agonist ABT-126 in mild-to-moderate Alzheimer's dementia. Alzheimer's & Dementia: Translational Research & Clinical Interventions 1, 81-90. Ghiso, J., Rostagno, A., Gardella, J. E., Liem, L., Gorevic, P. D. and Frangione, B. (1992) A 109-amino-acid Cterminal fragment of Alzheimer's-disease amyloid precursor protein contains a sequence, -RHDS-, that promotes cell adhesion. The Biochemical journal 288 ( Pt 3), 1053-1059. Ghiso, J., Rostagno, A., Tomidokoro, Y., Lashley, T., Bojsen-Moller, M., Braendgaard, H., Plant, G., Holton, J., Lal, R., Revesz, T. and Frangione, B. (2006) Genetic alterations of the BRI2 gene: familial British and Danish dementias. Brain pathology 16, 71-79. Gimbel, D. A., Nygaard, H. B., Coffey, E. E., Gunther, E. C., Lauren, J., Gimbel, Z. A. and Strittmatter, S. M. (2010) Memory impairment in transgenic Alzheimer mice requires cellular prion protein. The Journal of neuroscience : the official journal of the Society for Neuroscience 30, 6367-6374. Golabek, A., Marques, M. A., Lalowski, M. and Wisniewski, T. (1995) Amyloid beta binding proteins in vitro and in normal human cerebrospinal fluid. Neuroscience letters 191, 79-82. Gordon, S. (2002) Pattern recognition receptors: doubling up for the innate immune response. Cell 111, 927-930. Gouras, G. K., Tsai, J., Naslund, J., Vincent, B., Edgar, M., Checler, F., Greenfield, J. P., Haroutunian, V., Buxbaum, J. D., Xu, H., Greengard, P. and Relkin, N. R. (2000) Intraneuronal Abeta42 accumulation in human brain. The American journal of pathology 156, 15-20. Gupta, V. B., Laws, S. M., Villemagne, V. L., Ames, D., Bush, A. I., Ellis, K. A., Lui, J. K., Masters, C., Rowe, C. C., Szoeke, C., Taddei, K., Martins, R. N. and Group, A. R. (2011) Plasma apolipoprotein E and Alzheimer disease risk: the AIBL study of aging. Neurology 76, 1091-1098. Halestrap, A. P., McStay, G. P. and Clarke, S. J. (2002) The permeability transition pore complex: another view. Biochimie 84, 153-166. Hammad, S. M., Ranganathan, S., Loukinova, E., Twal, W. O. and Argraves, W. S. (1997) Interaction of apolipoprotein J-amyloid beta-peptide complex with low density lipoprotein receptor-related protein2/megalin. A mechanism to prevent pathological accumulation of amyloid beta-peptide. The Journal of biological chemistry 272, 18644-18649.
Page 49 of 68
Ac ce pt e
d
M
an
us
cr
ip t
Han, S. H., Jung, E. S., Sohn, J. H., Hong, H. J., Hong, H. S., Kim, J. W., Na, D. L., Kim, M., Kim, H., Ha, H. J., Kim, Y. H., Huh, N., Jung, M. W. and Mook-Jung, I. (2011a) Human serum transthyretin levels correlate inversely with Alzheimer's disease. Journal of Alzheimer's disease : JAD 25, 77-84. Han, S. H., Kim, J. S., Lee, Y., Choi, H., Kim, J. W., Na, D. L., Yang, E. G., Yu, M. H., Hwang, D., Lee, C. and Mook-Jung, I. (2014) Both targeted mass spectrometry and flow sorting analysis methods detected the decreased serum apolipoprotein e level in Alzheimer's disease patients. Molecular & cellular proteomics : MCP 13, 407-419. Han, S. H., Kim, Y. H. and Mook-Jung, I. (2011b) RAGE: the beneficial and deleterious effects by diverse mechanisms of actions. Molecules and cells 31, 91-97. Hansson, S. F., Andreasson, U., Wall, M., Skoog, I., Andreasen, N., Wallin, A., Zetterberg, H. and Blennow, K. (2009) Reduced levels of amyloid-beta-binding proteins in cerebrospinal fluid from Alzheimer's disease patients. Journal of Alzheimer's disease : JAD 16, 389-397. Henderson, J. T., Georgiou, J., Jia, Z., Robertson, J., Elowe, S., Roder, J. C. and Pawson, T. (2001) The receptor tyrosine kinase EphB2 regulates NMDA-dependent synaptic function. Neuron 32, 1041-1056. Henry-Mowatt, J., Dive, C., Martinou, J. C. and James, D. (2004) Role of mitochondrial membrane permeabilization in apoptosis and cancer. Oncogene 23, 2850-2860. Herber, D. L., Mercer, M., Roth, L. M., Symmonds, K., Maloney, J., Wilson, N., Freeman, M. J., Morgan, D. and Gordon, M. N. (2007) Microglial activation is required for Abeta clearance after intracranial injection of lipopolysaccharide in APP transgenic mice. Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology 2, 222-231. Hernandez-Zimbron, L. F., Luna-Munoz, J., Mena, R., Vazquez-Ramirez, R., Kubli-Garfias, C., Cribbs, D. H., Manoutcharian, K. and Gevorkian, G. (2012) Amyloid-beta peptide binds to cytochrome C oxidase subunit 1. PloS one 7, e42344. Herold, K., Moser, B., Chen, Y., Zeng, S., Yan, S. F., Ramasamy, R., Emond, J., Clynes, R. and Schmidt, A. M. (2007) Receptor for advanced glycation end products (RAGE) in a dash to the rescue: inflammatory signals gone awry in the primal response to stress. Journal of leukocyte biology 82, 204-212. Herz, J. and Marschang, P. (2003) Coaxing the LDL receptor family into the fold. Cell 112, 289-292. Herz, J. and Strickland, D. K. (2001) LRP: a multifunctional scavenger and signaling receptor. The Journal of clinical investigation 108, 779-784. Hesse, C., Larsson, H., Fredman, P., Minthon, L., Andreasen, N., Davidsson, P. and Blennow, K. (2000) Measurement of apolipoprotein E (apoE) in cerebrospinal fluid. Neurochemical research 25, 511-517. Hodge, T. and Colombini, M. (1997) Regulation of metabolite flux through voltage-gating of VDAC channels. The Journal of membrane biology 157, 271-279. Holtzman, D. M., Bales, K. R., Tenkova, T., Fagan, A. M., Parsadanian, M., Sartorius, L. J., Mackey, B., Olney, J., McKeel, D., Wozniak, D. and Paul, S. M. (2000) Apolipoprotein E isoform-dependent amyloid deposition and neuritic degeneration in a mouse model of Alzheimer's disease. Proceedings of the National Academy of Sciences of the United States of America 97, 2892-2897. Holtzman, D. M., Bales, K. R., Wu, S., Bhat, P., Parsadanian, M., Fagan, A. M., Chang, L. K., Sun, Y. and Paul, S. M. (1999) Expression of human apolipoprotein E reduces amyloid-beta deposition in a mouse model of Alzheimer's disease. The Journal of clinical investigation 103, R15-R21. Hone, E., Martins, I. J., Fonte, J. and Martins, R. N. (2003) Apolipoprotein E influences amyloid-beta clearance from the murine periphery. Journal of Alzheimer's disease : JAD 5, 1-8. Hong, S., Ostaszewski, B. L., Yang, T., O'Malley, T. T., Jin, M., Yanagisawa, K., Li, S., Bartels, T. and Selkoe, D. J. (2014) Soluble Abeta oligomers are rapidly sequestered from brain ISF in vivo and bind GM1 ganglioside on cellular membranes. Neuron 82, 308-319. Hou, L. and Zagorski, M. G. (2006) NMR reveals anomalous copper(II) binding to the amyloid Abeta peptide of Alzheimer's disease. Journal of the American Chemical Society 128, 9260-9261. House, E., Collingwood, J., Khan, A., Korchazkina, O., Berthon, G. and Exley, C. (2004) Aluminium, iron, zinc and copper influence the in vitro formation of amyloid fibrils of Abeta42 in a manner which may have consequences for metal chelation therapy in Alzheimer's disease. Journal of Alzheimer's disease : JAD 6, 291-301. Huang, X., Cuajungco, M. P., Atwood, C. S., Moir, R. D., Tanzi, R. E. and Bush, A. I. (2000) Alzheimer's disease, beta-amyloid protein and zinc. The Journal of nutrition 130, 1488S-1492S. Hughes, S. R., Khorkova, O., Goyal, S., Knaeblein, J., Heroux, J., Riedel, N. G. and Sahasrabudhe, S. (1998) Alpha2-macroglobulin associates with beta-amyloid peptide and prevents fibril formation. Proceedings of the National Academy of Sciences of the United States of America 95, 3275-3280. Hureau, C. and Faller, P. (2009) Abeta-mediated ROS production by Cu ions: structural insights, mechanisms and relevance to Alzheimer's disease. Biochimie 91, 1212-1217. Huttunen, H. J., Fages, C. and Rauvala, H. (1999) Receptor for advanced glycation end products (RAGE)-
Page 50 of 68
Ac ce pt e
d
M
an
us
cr
ip t
mediated neurite outgrowth and activation of NF-kappaB require the cytoplasmic domain of the receptor but different downstream signaling pathways. The Journal of biological chemistry 274, 1991919924. Hye, A., Lynham, S., Thambisetty, M., Causevic, M., Campbell, J., Byers, H. L., Hooper, C., Rijsdijk, F., Tabrizi, S. J., Banner, S., Shaw, C. E., Foy, C., Poppe, M., Archer, N., Hamilton, G., Powell, J., Brown, R. G., Sham, P., Ward, M. and Lovestone, S. (2006) Proteome-based plasma biomarkers for Alzheimer's disease. Brain : a journal of neurology 129, 3042-3050. Isberg, R. R. and Tran Van Nhieu, G. (1994) Binding and internalization of microorganisms by integrin receptors. Trends in microbiology 2, 10-14. Jan, A., Gokce, O., Luthi-Carter, R. and Lashuel, H. A. (2008) The ratio of monomeric to aggregated forms of Abeta40 and Abeta42 is an important determinant of amyloid-beta aggregation, fibrillogenesis, and toxicity. The Journal of biological chemistry 283, 28176-28189. Jana, M., Palencia, C. A. and Pahan, K. (2008) Fibrillar amyloid-beta peptides activate microglia via TLR2: implications for Alzheimer's disease. Journal of immunology 181, 7254-7262. Janciauskiene, S., Garcia de Frutos, P., Carlemalm, E., Dahlback, B. and Eriksson, S. (1995) Inhibition of Alzheimer beta-peptide fibril formation by serum amyloid P component. The Journal of biological chemistry 270, 26041-26044. Janciauskiene, S., Rubin, H., Lukacs, C. M. and Wright, H. T. (1998) Alzheimer's peptide Abeta1-42 binds to two beta-sheets of alpha1-antichymotrypsin and transforms it from inhibitor to substrate. The Journal of biological chemistry 273, 28360-28364. Jiang, Q., Lee, C. Y., Mandrekar, S., Wilkinson, B., Cramer, P., Zelcer, N., Mann, K., Lamb, B., Willson, T. M., Collins, J. L., Richardson, J. C., Smith, J. D., Comery, T. A., Riddell, D., Holtzman, D. M., Tontonoz, P. and Landreth, G. E. (2008) ApoE promotes the proteolytic degradation of Abeta. Neuron 58, 681-693. Joslin, G., Griffin, G. L., August, A. M., Adams, S., Fallon, R. J., Senior, R. M. and Perlmutter, D. H. (1992) The serpin-enzyme complex (SEC) receptor mediates the neutrophil chemotactic effect of alpha-1 antitrypsin-elastase complexes and amyloid-beta peptide. The Journal of clinical investigation 90, 1150-1154. Kakio, A., Nishimoto, S., Yanagisawa, K., Kozutsumi, Y. and Matsuzaki, K. (2002) Interactions of amyloid beta-protein with various gangliosides in raft-like membranes: importance of GM1 ganglioside-bound form as an endogenous seed for Alzheimer amyloid. Biochemistry 41, 7385-7390. Kalaria, R. N. and Perry, G. (1993) Amyloid P component and other acute-phase proteins associated with cerebellar A beta-deposits in Alzheimer's disease. Brain research 631, 151-155. Kallhoff, V., Peethumnongsin, E. and Zheng, H. (2007) Lack of alpha-synuclein increases amyloid plaque accumulation in a transgenic mouse model of Alzheimer's disease. Molecular neurodegeneration 2, 6. Kanekiyo, T., Cirrito, J. R., Liu, C. C., Shinohara, M., Li, J., Schuler, D. R., Shinohara, M., Holtzman, D. M. and Bu, G. (2013) Neuronal clearance of amyloid-beta by endocytic receptor LRP1. The Journal of neuroscience : the official journal of the Society for Neuroscience 33, 19276-19283. Kang, J., Lemaire, H. G., Unterbeck, A., Salbaum, J. M., Masters, C. L., Grzeschik, K. H., Multhaup, G., Beyreuther, K. and Muller-Hill, B. (1987) The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor. Nature 325, 733-736. Kariko, K., Weissman, D. and Welsh, F. A. (2004) Inhibition of toll-like receptor and cytokine signaling--a unifying theme in ischemic tolerance. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 24, 1288-1304. Kawahara, M., Muramoto, K., Kobayashi, K., Mori, H. and Kuroda, Y. (1994) Aluminum promotes the aggregation of Alzheimer's amyloid beta-protein in vitro. Biochemical and biophysical research communications 198, 531-535. Kawamoto, E. M., Lepsch, L. B., Boaventura, M. F., Munhoz, C. D., Lima, L. S., Yshii, L. M., Avellar, M. C., Curi, R., Mattson, M. P. and Scavone, C. (2008) Amyloid beta-peptide activates nuclear factor-kappaB through an N-methyl-D-aspartate signaling pathway in cultured cerebellar cells. Journal of neuroscience research 86, 845-860. Kawarabayashi, T., Younkin, L. H., Saido, T. C., Shoji, M., Ashe, K. H. and Younkin, S. G. (2001) Agedependent changes in brain, CSF, and plasma amyloid (beta) protein in the Tg2576 transgenic mouse model of Alzheimer's disease. The Journal of neuroscience : the official journal of the Society for Neuroscience 21, 372-381. Kessler, H., Bayer, T. A., Bach, D., Schneider-Axmann, T., Supprian, T., Herrmann, W., Haber, M., Multhaup, G., Falkai, P. and Pajonk, F. G. (2008) Intake of copper has no effect on cognition in patients with mild Alzheimer's disease: a pilot phase 2 clinical trial. Journal of neural transmission 115, 1181-1187. Khan, G. M., Tong, M., Jhun, M., Arora, K. and Nichols, R. A. (2010) beta-Amyloid activates presynaptic alpha7 nicotinic acetylcholine receptors reconstituted into a model nerve cell system: involvement of
Page 51 of 68
Ac ce pt e
d
M
an
us
cr
ip t
lipid rafts. The European journal of neuroscience 31, 788-796. Kim, J., Basak, J. M. and Holtzman, D. M. (2009) The role of apolipoprotein E in Alzheimer's disease. Neuron 63, 287-303. Kim, J., Jiang, H., Park, S., Eltorai, A. E., Stewart, F. R., Yoon, H., Basak, J. M., Finn, M. B. and Holtzman, D. M. (2011) Haploinsufficiency of human APOE reduces amyloid deposition in a mouse model of amyloid-beta amyloidosis. The Journal of neuroscience : the official journal of the Society for Neuroscience 31, 18007-18012. Kim, J., Miller, V. M., Levites, Y., West, K. J., Zwizinski, C. W., Moore, B. D., Troendle, F. J., Bann, M., Verbeeck, C., Price, R. W., Smithson, L., Sonoda, L., Wagg, K., Rangachari, V., Zou, F., Younkin, S. G., Graff-Radford, N., Dickson, D., Rosenberry, T. and Golde, T. E. (2008) BRI2 (ITM2b) inhibits Abeta deposition in vivo. The Journal of neuroscience : the official journal of the Society for Neuroscience 28, 6030-6036. Kim, J., Onstead, L., Randle, S., Price, R., Smithson, L., Zwizinski, C., Dickson, D. W., Golde, T. and McGowan, E. (2007) Abeta40 inhibits amyloid deposition in vivo. The Journal of neuroscience : the official journal of the Society for Neuroscience 27, 627-633. Kim, T., Vidal, G. S., Djurisic, M., William, C. M., Birnbaum, M. E., Garcia, K. C., Hyman, B. T. and Shatz, C. J. (2013) Human LilrB2 is a beta-amyloid receptor and its murine homolog PirB regulates synaptic plasticity in an Alzheimer's model. Science 341, 1399-1404. Kim, T. S., Pae, C. U., Yoon, S. J., Jang, W. Y., Lee, N. J., Kim, J. J., Lee, S. J., Lee, C., Paik, I. H. and Lee, C. U. (2006) Decreased plasma antioxidants in patients with Alzheimer's disease. International journal of geriatric psychiatry 21, 344-348. Kitazawa, M., Cheng, D. and Laferla, F. M. (2009) Chronic copper exposure exacerbates both amyloid and tau pathology and selectively dysregulates cdk5 in a mouse model of AD. Journal of neurochemistry 108, 1550-1560. Klann, E. (2002) Metaplastic protein phosphatases. Learning & memory 9, 153-155. Koenigsknecht, J. and Landreth, G. (2004) Microglial phagocytosis of fibrillar beta-amyloid through a beta1 integrin-dependent mechanism. The Journal of neuroscience : the official journal of the Society for Neuroscience 24, 9838-9846. Kook, S. Y., Hong, H. S., Moon, M., Ha, C. M., Chang, S. and Mook-Jung, I. (2012) Abeta(1)(-)(4)(2)-RAGE interaction disrupts tight junctions of the blood-brain barrier via Ca(2)(+)-calcineurin signaling. The Journal of neuroscience : the official journal of the Society for Neuroscience 32, 8845-8854. Korchazhkina, O. V., Ashcroft, A. E., Kiss, T. and Exley, C. (2002) The degradation of Abeta(25-35) by the serine protease plasmin is inhibited by aluminium. Journal of Alzheimer's disease : JAD 4, 357-367. Kovacs, D. M. (2000) alpha2-macroglobulin in late-onset Alzheimer's disease. Experimental gerontology 35, 473-479. Kozin, S. A., Zirah, S., Rebuffat, S., Hoa, G. H. and Debey, P. (2001) Zinc binding to Alzheimer's Abeta(1-16) peptide results in stable soluble complex. Biochemical and biophysical research communications 285, 959-964. Kudo, W., Lee, H. P., Zou, W. Q., Wang, X., Perry, G., Zhu, X., Smith, M. A., Petersen, R. B. and Lee, H. G. (2012) Cellular prion protein is essential for oligomeric amyloid-beta-induced neuronal cell death. Human molecular genetics 21, 1138-1144. Kuo, Y. M., Kokjohn, T. A., Kalback, W., Luehrs, D., Galasko, D. R., Chevallier, N., Koo, E. H., Emmerling, M. R. and Roher, A. E. (2000) Amyloid-beta peptides interact with plasma proteins and erythrocytes: implications for their quantitation in plasma. Biochemical and biophysical research communications 268, 750-756. Kurochkin, I. V. (1998) Amyloidogenic determinant as a substrate recognition motif of insulin-degrading enzyme. FEBS letters 427, 153-156. Kuszczyk, M. A., Sanchez, S., Pankiewicz, J., Kim, J., Duszczyk, M., Guridi, M., Asuni, A. A., Sullivan, P. M., Holtzman, D. M. and Sadowski, M. J. (2013) Blocking the interaction between apolipoprotein E and Abeta reduces intraneuronal accumulation of Abeta and inhibits synaptic degeneration. The American journal of pathology 182, 1750-1768. Lacor, P. N., Buniel, M. C., Furlow, P. W., Clemente, A. S., Velasco, P. T., Wood, M., Viola, K. L. and Klein, W. L. (2007) Abeta oligomer-induced aberrations in synapse composition, shape, and density provide a molecular basis for loss of connectivity in Alzheimer's disease. The Journal of neuroscience : the official journal of the Society for Neuroscience 27, 796-807. LaDu, M. J., Falduto, M. T., Manelli, A. M., Reardon, C. A., Getz, G. S. and Frail, D. E. (1994) Isoform-specific binding of apolipoprotein E to beta-amyloid. The Journal of biological chemistry 269, 23403-23406. LaFerla, F. M., Green, K. N. and Oddo, S. (2007) Intracellular amyloid-beta in Alzheimer's disease. Nature reviews. Neuroscience 8, 499-509.
Page 52 of 68
Ac ce pt e
d
M
an
us
cr
ip t
Lannfelt, L., Blennow, K., Zetterberg, H., Batsman, S., Ames, D., Harrison, J., Masters, C. L., Targum, S., Bush, A. I., Murdoch, R., Wilson, J., Ritchie, C. W. and group, P. E. s. (2008) Safety, efficacy, and biomarker findings of PBT2 in targeting Abeta as a modifying therapy for Alzheimer's disease: a phase IIa, double-blind, randomised, placebo-controlled trial. Lancet neurology 7, 779-786. Lauer, D., Reichenbach, A. and Birkenmeier, G. (2001) Alpha 2-macroglobulin-mediated degradation of amyloid beta 1--42: a mechanism to enhance amyloid beta catabolism. Experimental neurology 167, 385-392. Lauren, J., Gimbel, D. A., Nygaard, H. B., Gilbert, J. W. and Strittmatter, S. M. (2009) Cellular prion protein mediates impairment of synaptic plasticity by amyloid-beta oligomers. Nature 457, 1128-1132. Le, Y., Gong, W., Tiffany, H. L., Tumanov, A., Nedospasov, S., Shen, W., Dunlop, N. M., Gao, J. L., Murphy, P. M., Oppenheim, J. J. and Wang, J. M. (2001) Amyloid (beta)42 activates a G-protein-coupled chemoattractant receptor, FPR-like-1. The Journal of neuroscience : the official journal of the Society for Neuroscience 21, RC123. Lee, D. H. and Wang, H. Y. (2003) Differential physiologic responses of alpha7 nicotinic acetylcholine receptors to beta-amyloid1-40 and beta-amyloid1-42. Journal of neurobiology 55, 25-30. Lei, P., Ayton, S., Finkelstein, D. I., Spoerri, L., Ciccotosto, G. D., Wright, D. K., Wong, B. X., Adlard, P. A., Cherny, R. A., Lam, L. Q., Roberts, B. R., Volitakis, I., Egan, G. F., McLean, C. A., Cappai, R., Duce, J. A. and Bush, A. I. (2012) Tau deficiency induces parkinsonism with dementia by impairing APPmediated iron export. Nature medicine 18, 291-295. Letiembre, M., Liu, Y., Walter, S., Hao, W., Pfander, T., Wrede, A., Schulz-Schaeffer, W. and Fassbender, K. (2009) Screening of innate immune receptors in neurodegenerative diseases: a similar pattern. Neurobiology of aging 30, 759-768. Ling, X., Martins, R. N., Racchi, M., Craft, S. and Helmerhorst, E. (2002) Amyloid beta antagonizes insulin promoted secretion of the amyloid beta protein precursor. Journal of Alzheimer's disease : JAD 4, 369374. Liu, Q., Kawai, H. and Berg, D. K. (2001) beta -Amyloid peptide blocks the response of alpha 7-containing nicotinic receptors on hippocampal neurons. Proceedings of the National Academy of Sciences of the United States of America 98, 4734-4739. Liu, Q., Trotter, J., Zhang, J., Peters, M. M., Cheng, H., Bao, J., Han, X., Weeber, E. J. and Bu, G. (2010) Neuronal LRP1 knockout in adult mice leads to impaired brain lipid metabolism and progressive, agedependent synapse loss and neurodegeneration. The Journal of neuroscience : the official journal of the Society for Neuroscience 30, 17068-17078. Liu, S., Liu, Y., Hao, W., Wolf, L., Kiliaan, A. J., Penke, B., Rube, C. E., Walter, J., Heneka, M. T., Hartmann, T., Menger, M. D. and Fassbender, K. (2012) TLR2 is a primary receptor for Alzheimer's amyloid beta peptide to trigger neuroinflammatory activation. Journal of immunology 188, 1098-1107. Llewellyn, D. J., Langa, K. M., Friedland, R. P. and Lang, I. A. (2010) Serum albumin concentration and cognitive impairment. Current Alzheimer research 7, 91-96. Lorenzo, A., Yuan, M., Zhang, Z., Paganetti, P. A., Sturchler-Pierrat, C., Staufenbiel, M., Mautino, J., Vigo, F. S., Sommer, B. and Yankner, B. A. (2000) Amyloid beta interacts with the amyloid precursor protein: a potential toxic mechanism in Alzheimer's disease. Nature neuroscience 3, 460-464. Lovell, M. A., Robertson, J. D., Teesdale, W. J., Campbell, J. L. and Markesbery, W. R. (1998) Copper, iron and zinc in Alzheimer's disease senile plaques. Journal of the neurological sciences 158, 47-52. Lue, L. F., Walker, D. G., Brachova, L., Beach, T. G., Rogers, J., Schmidt, A. M., Stern, D. M. and Yan, S. D. (2001) Involvement of microglial receptor for advanced glycation endproducts (RAGE) in Alzheimer's disease: identification of a cellular activation mechanism. Experimental neurology 171, 29-45. Lustbader, J. W., Cirilli, M., Lin, C., Xu, H. W., Takuma, K., Wang, N., Caspersen, C., Chen, X., Pollak, S., Chaney, M., Trinchese, F., Liu, S., Gunn-Moore, F., Lue, L. F., Walker, D. G., Kuppusamy, P., Zewier, Z. L., Arancio, O., Stern, D., Yan, S. S. and Wu, H. (2004) ABAD directly links Abeta to mitochondrial toxicity in Alzheimer's disease. Science 304, 448-452. Ma, J., Yee, A., Brewer, H. B., Jr., Das, S. and Potter, H. (1994) Amyloid-associated proteins alpha 1antichymotrypsin and apolipoprotein E promote assembly of Alzheimer beta-protein into filaments. Nature 372, 92-94. Ma, Q. F., Li, Y. M., Du, J. T., Kanazawa, K., Nemoto, T., Nakanishi, H. and Zhao, Y. F. (2005) Binding of copper (II) ion to an Alzheimer's tau peptide as revealed by MALDI-TOF MS, CD, and NMR. Biopolymers 79, 74-85. Mackic, J. B., Stins, M., McComb, J. G., Calero, M., Ghiso, J., Kim, K. S., Yan, S. D., Stern, D., Schmidt, A. M., Frangione, B. and Zlokovic, B. V. (1998) Human blood-brain barrier receptors for Alzheimer's amyloid-beta 1- 40. Asymmetrical binding, endocytosis, and transcytosis at the apical side of brain microvascular endothelial cell monolayer. The Journal of clinical investigation 102, 734-743.
Page 53 of 68
Ac ce pt e
d
M
an
us
cr
ip t
Maes, M., DeVos, N., Wauters, A., Demedts, P., Maurits, V. W., Neels, H., Bosmans, E., Altamura, C., Lin, A., Song, C., Vandenbroucke, M. and Scharpe, S. (1999) Inflammatory markers in younger vs elderly normal volunteers and in patients with Alzheimer's disease. Journal of psychiatric research 33, 397405. Manczak, M., Calkins, M. J. and Reddy, P. H. (2011) Impaired mitochondrial dynamics and abnormal interaction of amyloid beta with mitochondrial protein Drp1 in neurons from patients with Alzheimer's disease: implications for neuronal damage. Human molecular genetics 20, 2495-2509. Manczak, M. and Reddy, P. H. (2012a) Abnormal interaction between the mitochondrial fission protein Drp1 and hyperphosphorylated tau in Alzheimer's disease neurons: implications for mitochondrial dysfunction and neuronal damage. Human molecular genetics 21, 2538-2547. Manczak, M. and Reddy, P. H. (2012b) Abnormal interaction of VDAC1 with amyloid beta and phosphorylated tau causes mitochondrial dysfunction in Alzheimer's disease. Human molecular genetics 21, 5131-5146. Mandal, P. K., Pettegrew, J. W., Masliah, E., Hamilton, R. L. and Mandal, R. (2006) Interaction between Abeta peptide and alpha synuclein: molecular mechanisms in overlapping pathology of Alzheimer's and Parkinson's in dementia with Lewy body disease. Neurochemical research 31, 1153-1162. Mantyh, P. W., Ghilardi, J. R., Rogers, S., DeMaster, E., Allen, C. J., Stimson, E. R. and Maggio, J. E. (1993) Aluminum, iron, and zinc ions promote aggregation of physiological concentrations of beta-amyloid peptide. Journal of neurochemistry 61, 1171-1174. Marques, M. A., Kulstad, J. J., Savard, C. E., Green, P. S., Lee, S. P., Craft, S., Watson, G. S. and Cook, D. G. (2009) Peripheral amyloid-beta levels regulate amyloid-beta clearance from the central nervous system. Journal of Alzheimer's disease : JAD 16, 325-329. Martic, S., Rains, M. K. and Kraatz, H. B. (2013) Probing copper/tau protein interactions electrochemically. Analytical biochemistry 442, 130-137. Masliah, E., Rockenstein, E., Veinbergs, I., Sagara, Y., Mallory, M., Hashimoto, M. and Mucke, L. (2001) betaamyloid peptides enhance alpha-synuclein accumulation and neuronal deficits in a transgenic mouse model linking Alzheimer's disease and Parkinson's disease. Proceedings of the National Academy of Sciences of the United States of America 98, 12245-12250. Matsubara, E., Frangione, B. and Ghiso, J. (1995) Characterization of apolipoprotein J-Alzheimer's A beta interaction. The Journal of biological chemistry 270, 7563-7567. Matsuoka, Y., Saito, M., LaFrancois, J., Saito, M., Gaynor, K., Olm, V., Wang, L., Casey, E., Lu, Y., Shiratori, C., Lemere, C. and Duff, K. (2003) Novel therapeutic approach for the treatment of Alzheimer's disease by peripheral administration of agents with an affinity to beta-amyloid. The Journal of neuroscience : the official journal of the Society for Neuroscience 23, 29-33. Matter, M. L., Zhang, Z., Nordstedt, C. and Ruoslahti, E. (1998) The alpha5beta1 integrin mediates elimination of amyloid-beta peptide and protects against apoptosis. The Journal of cell biology 141, 1019-1030. Mawuenyega, K. G., Sigurdson, W., Ovod, V., Munsell, L., Kasten, T., Morris, J. C., Yarasheski, K. E. and Bateman, R. J. (2010) Decreased clearance of CNS beta-amyloid in Alzheimer's disease. Science 330, 1774. May, P. C., Lampert-Etchells, M., Johnson, S. A., Poirier, J., Masters, J. N. and Finch, C. E. (1990) Dynamics of gene expression for a hippocampal glycoprotein elevated in Alzheimer's disease and in response to experimental lesions in rat. Neuron 5, 831-839. McDonald, D. R., Brunden, K. R. and Landreth, G. E. (1997) Amyloid fibrils activate tyrosine kinase-dependent signaling and superoxide production in microglia. The Journal of neuroscience : the official journal of the Society for Neuroscience 17, 2284-2294. McGeer, P. L., Kawamata, T. and Walker, D. G. (1992) Distribution of clusterin in Alzheimer brain tissue. Brain research 579, 337-341. Medzhitov, R. (2001) Toll-like receptors and innate immunity. Nature reviews. Immunology 1, 135-145. Mehta, T. K., Dougherty, J. J., Wu, J., Choi, C. H., Khan, G. M. and Nichols, R. A. (2009) Defining pre-synaptic nicotinic receptors regulated by beta amyloid in mouse cortex and hippocampus with receptor null mutants. Journal of neurochemistry 109, 1452-1458. Michaud, J. P., Halle, M., Lampron, A., Theriault, P., Prefontaine, P., Filali, M., Tribout-Jover, P., Lanteigne, A. M., Jodoin, R., Cluff, C., Brichard, V., Palmantier, R., Pilorget, A., Larocque, D. and Rivest, S. (2013) Toll-like receptor 4 stimulation with the detoxified ligand monophosphoryl lipid A improves Alzheimer's disease-related pathology. Proceedings of the National Academy of Sciences of the United States of America 110, 1941-1946. Mick, D. U., Fox, T. D. and Rehling, P. (2011) Inventory control: cytochrome c oxidase assembly regulates mitochondrial translation. Nature reviews. Molecular cell biology 12, 14-20. Milward, E. A., Papadopoulos, R., Fuller, S. J., Moir, R. D., Small, D., Beyreuther, K. and Masters, C. L. (1992) The amyloid protein precursor of Alzheimer's disease is a mediator of the effects of nerve growth factor
Page 54 of 68
Ac ce pt e
d
M
an
us
cr
ip t
on neurite outgrowth. Neuron 9, 129-137. Mizuno, T. (2012) The biphasic role of microglia in Alzheimer's disease. International journal of Alzheimer's disease 2012, 737846. Mold, M., Shrive, A. K. and Exley, C. (2012) Serum amyloid P component accelerates the formation and enhances the stability of amyloid fibrils in a physiologically significant under-saturated solution of amyloid-beta42. Journal of Alzheimer's disease : JAD 29, 875-881. Moreira, P. I., Santos, M. S., Moreno, A., Rego, A. C. and Oliveira, C. (2002) Effect of amyloid beta-peptide on permeability transition pore: a comparative study. Journal of neuroscience research 69, 257-267. Morgan, D., Gordon, M. N., Tan, J., Wilcock, D. and Rojiani, A. M. (2005) Dynamic complexity of the microglial activation response in transgenic models of amyloid deposition: implications for Alzheimer therapeutics. Journal of neuropathology and experimental neurology 64, 743-753. Murray, M. M., Bernstein, S. L., Nyugen, V., Condron, M. M., Teplow, D. B. and Bowers, M. T. (2009) Amyloid beta protein: Abeta40 inhibits Abeta42 oligomerization. Journal of the American Chemical Society 131, 6316-6317. Neri, L. C. and Hewitt, D. (1991) Aluminium, Alzheimer's disease, and drinking water. Lancet 338, 390. Nicoll, A. J., Panico, S., Freir, D. B., Wright, D., Terry, C., Risse, E., Herron, C. E., O'Malley, T., Wadsworth, J. D., Farrow, M. A., Walsh, D. M., Saibil, H. R. and Collinge, J. (2013) Amyloid-beta nanotubes are associated with prion protein-dependent synaptotoxicity. Nature communications 4, 2416. Nilsson, L. N., Bales, K. R., DiCarlo, G., Gordon, M. N., Morgan, D., Paul, S. M. and Potter, H. (2001) Alpha1-antichymotrypsin promotes beta-sheet amyloid plaque deposition in a transgenic mouse model of Alzheimer's disease. The Journal of neuroscience : the official journal of the Society for Neuroscience 21, 1444-1451. Oda, T., Pasinetti, G. M., Osterburg, H. H., Anderson, C., Johnson, S. A. and Finch, C. E. (1994) Purification and characterization of brain clusterin. Biochemical and biophysical research communications 204, 1131-1136. Ono, K., Noguchi-Shinohara, M., Yoshita, M., Naiki, H. and Yamada, M. (2007) Cerebrospinal fluid of Alzheimer's disease and dementia with Lewy bodies patients enhances alpha-synuclein fibril formation in vitro. Experimental neurology 203, 579-583. Ono, K., Takahashi, R., Ikeda, T. and Yamada, M. (2012) Cross-seeding effects of amyloid beta-protein and alpha-synuclein. Journal of neurochemistry 122, 883-890. Origlia, N., Bonadonna, C., Rosellini, A., Leznik, E., Arancio, O., Yan, S. S. and Domenici, L. (2010) Microglial receptor for advanced glycation end product-dependent signal pathway drives beta-amyloid-induced synaptic depression and long-term depression impairment in entorhinal cortex. The Journal of neuroscience : the official journal of the Society for Neuroscience 30, 11414-11425. Origlia, N., Righi, M., Capsoni, S., Cattaneo, A., Fang, F., Stern, D. M., Chen, J. X., Schmidt, A. M., Arancio, O., Yan, S. D. and Domenici, L. (2008) Receptor for advanced glycation end product-dependent activation of p38 mitogen-activated protein kinase contributes to amyloid-beta-mediated cortical synaptic dysfunction. The Journal of neuroscience : the official journal of the Society for Neuroscience 28, 3521-3530. Palop, J. J. and Mucke, L. (2010) Amyloid-beta-induced neuronal dysfunction in Alzheimer's disease: from synapses toward neural networks. Nature neuroscience 13, 812-818. Panegyres, P. K. (2001) The functions of the amyloid precursor protein gene. Reviews in the neurosciences 12, 1-39. Pankiewicz, J. E., Guridi, M., Kim, J., Asuni, A. A., Sanchez, S., Sullivan, P. M., Holtzman, D. M. and Sadowski, M. J. (2014) Blocking the apoE/Abeta interaction ameliorates Abeta-related pathology in APOE epsilon2 and epsilon4 targeted replacement Alzheimer model mice. Acta neuropathologica communications 2, 75. Paresce, D. M., Ghosh, R. N. and Maxfield, F. R. (1996) Microglial cells internalize aggregates of the Alzheimer's disease amyloid beta-protein via a scavenger receptor. Neuron 17, 553-565. Park, L., Wang, G., Zhou, P., Zhou, J., Pitstick, R., Previti, M. L., Younkin, L., Younkin, S. G., Van Nostrand, W. E., Cho, S., Anrather, J., Carlson, G. A. and Iadecola, C. (2011) Scavenger receptor CD36 is essential for the cerebrovascular oxidative stress and neurovascular dysfunction induced by amyloid-beta. Proceedings of the National Academy of Sciences of the United States of America 108, 5063-5068. Park, L., Zhou, J., Zhou, P., Pistick, R., El Jamal, S., Younkin, L., Pierce, J., Arreguin, A., Anrather, J., Younkin, S. G., Carlson, G. A., McEwen, B. S. and Iadecola, C. (2013) Innate immunity receptor CD36 promotes cerebral amyloid angiopathy. Proceedings of the National Academy of Sciences of the United States of America 110, 3089-3094. Parks, J. K., Smith, T. S., Trimmer, P. A., Bennett, J. P., Jr. and Parker, W. D., Jr. (2001) Neurotoxic Abeta peptides increase oxidative stress in vivo through NMDA-receptor and nitric-oxide-synthase
Page 55 of 68
Ac ce pt e
d
M
an
us
cr
ip t
mechanisms, and inhibit complex IV activity and induce a mitochondrial permeability transition in vitro. Journal of neurochemistry 76, 1050-1056. Pettit, D. L., Shao, Z. and Yakel, J. L. (2001) beta-Amyloid(1-42) peptide directly modulates nicotinic receptors in the rat hippocampal slice. The Journal of neuroscience : the official journal of the Society for Neuroscience 21, RC120. Pickrell, A. M., Fukui, H. and Moraes, C. T. (2009) The role of cytochrome c oxidase deficiency in ROS and amyloid plaque formation. Journal of bioenergetics and biomembranes 41, 453-456. Pinho, C. M., Teixeira, P. F. and Glaser, E. (2014) Mitochondrial import and degradation of amyloid-beta peptide. Biochimica et biophysica acta. Poelmans, G., Buitelaar, J. K., Pauls, D. L. and Franke, B. (2011) A theoretical molecular network for dyslexia: integrating available genetic findings. Molecular psychiatry 16, 365-382. Puchades, M., Hansson, S. F., Nilsson, C. L., Andreasen, N., Blennow, K. and Davidsson, P. (2003) Proteomic studies of potential cerebrospinal fluid protein markers for Alzheimer's disease. Brain research. Molecular brain research 118, 140-146. Qiu, Z., Strickland, D. K., Hyman, B. T. and Rebeck, G. W. (1999) Alpha2-macroglobulin enhances the clearance of endogenous soluble beta-amyloid peptide via low-density lipoprotein receptor-related protein in cortical neurons. Journal of neurochemistry 73, 1393-1398. Querfurth, H. W. and LaFerla, F. M. (2010) Alzheimer's disease. The New England journal of medicine 362, 329-344. Raman, B., Ban, T., Yamaguchi, K., Sakai, M., Kawai, T., Naiki, H. and Goto, Y. (2005) Metal ion-dependent effects of clioquinol on the fibril growth of an amyloid {beta} peptide. The Journal of biological chemistry 280, 16157-16162. Reed-Geaghan, E. G., Savage, J. C., Hise, A. G. and Landreth, G. E. (2009) CD14 and toll-like receptors 2 and 4 are required for fibrillar A{beta}-stimulated microglial activation. The Journal of neuroscience : the official journal of the Society for Neuroscience 29, 11982-11992. Religa, D., Strozyk, D., Cherny, R. A., Volitakis, I., Haroutunian, V., Winblad, B., Naslund, J. and Bush, A. I. (2006) Elevated cortical zinc in Alzheimer disease. Neurology 67, 69-75. Renkawek, K., Voorter, C. E., Bosman, G. J., van Workum, F. P. and de Jong, W. W. (1994) Expression of alpha B-crystallin in Alzheimer's disease. Acta neuropathologica 87, 155-160. Rezaei-Ghaleh, N., Giller, K., Becker, S. and Zweckstetter, M. (2011) Effect of zinc binding on beta-amyloid structure and dynamics: implications for Abeta aggregation. Biophysical journal 101, 1202-1211. Richard, K. L., Filali, M., Prefontaine, P. and Rivest, S. (2008) Toll-like receptor 2 acts as a natural innate immune receptor to clear amyloid beta 1-42 and delay the cognitive decline in a mouse model of Alzheimer's disease. The Journal of neuroscience : the official journal of the Society for Neuroscience 28, 5784-5793. Riehl, A., Nemeth, J., Angel, P. and Hess, J. (2009) The receptor RAGE: Bridging inflammation and cancer. Cell communication and signaling : CCS 7, 12. Rottkamp, C. A., Raina, A. K., Zhu, X., Gaier, E., Bush, A. I., Atwood, C. S., Chevion, M., Perry, G. and Smith, M. A. (2001) Redox-active iron mediates amyloid-beta toxicity. Free radical biology & medicine 30, 447-450. Rulon, L. L., Robertson, J. D., Lovell, M. A., Deibel, M. A., Ehmann, W. D. and Markesber, W. R. (2000) Serum zinc levels and Alzheimer's disease. Biological trace element research 75, 79-85. Rushworth, J. V., Griffiths, H. H., Watt, N. T. and Hooper, N. M. (2013) Prion protein-mediated toxicity of amyloid-beta oligomers requires lipid rafts and the transmembrane LRP1. The Journal of biological chemistry 288, 8935-8951. Sabbagh, M. N., Agro, A., Bell, J., Aisen, P. S., Schweizer, E. and Galasko, D. (2011) PF-04494700, an oral inhibitor of receptor for advanced glycation end products (RAGE), in Alzheimer disease. Alzheimer disease and associated disorders 25, 206-212. Sabo, S., Lambert, M. P., Kessey, K., Wade, W., Krafft, G. and Klein, W. L. (1995) Interaction of beta-amyloid peptides with integrins in a human nerve cell line. Neuroscience letters 184, 25-28. Saito, Y., Akiyama, M., Araki, Y., Sumioka, A., Shiono, M., Taru, H., Nakaya, T., Yamamoto, T. and Suzuki, T. (2011) Intracellular trafficking of the amyloid beta-protein precursor (APP) regulated by novel function of X11-like. PloS one 6, e22108. Sanan, D. A., Weisgraber, K. H., Russell, S. J., Mahley, R. W., Huang, D., Saunders, A., Schmechel, D., Wisniewski, T., Frangione, B., Roses, A. D. and et al. (1994) Apolipoprotein E associates with beta amyloid peptide of Alzheimer's disease to form novel monofibrils. Isoform apoE4 associates more efficiently than apoE3. The Journal of clinical investigation 94, 860-869. Santos, R. X., Correia, S. C., Wang, X., Perry, G., Smith, M. A., Moreira, P. I. and Zhu, X. (2010) A synergistic dysfunction of mitochondrial fission/fusion dynamics and mitophagy in Alzheimer's disease. Journal of
Page 56 of 68
Ac ce pt e
d
M
an
us
cr
ip t
Alzheimer's disease : JAD 20 Suppl 2, S401-412. Sayre, L. M., Perry, G., Harris, P. L., Liu, Y., Schubert, K. A. and Smith, M. A. (2000) In situ oxidative catalysis by neurofibrillary tangles and senile plaques in Alzheimer's disease: a central role for bound transition metals. Journal of neurochemistry 74, 270-279. Schinzel, A. C., Takeuchi, O., Huang, Z., Fisher, J. K., Zhou, Z., Rubens, J., Hetz, C., Danial, N. N., Moskowitz, M. A. and Korsmeyer, S. J. (2005) Cyclophilin D is a component of mitochondrial permeability transition and mediates neuronal cell death after focal cerebral ischemia. Proceedings of the National Academy of Sciences of the United States of America 102, 12005-12010. Schmidt, C., Lepsverdize, E., Chi, S. L., Das, A. M., Pizzo, S. V., Dityatev, A. and Schachner, M. (2008) Amyloid precursor protein and amyloid beta-peptide bind to ATP synthase and regulate its activity at the surface of neural cells. Molecular psychiatry 13, 953-969. Schwarzman, A. L. and Goldgaber, D. (1996) Interaction of transthyretin with amyloid beta-protein: binding and inhibition of amyloid formation. Ciba Foundation symposium 199, 146-160; discussion 160-144. Schwarzman, A. L., Gregori, L., Vitek, M. P., Lyubski, S., Strittmatter, W. J., Enghilde, J. J., Bhasin, R., Silverman, J., Weisgraber, K. H., Coyle, P. K. and et al. (1994) Transthyretin sequesters amyloid beta protein and prevents amyloid formation. Proceedings of the National Academy of Sciences of the United States of America 91, 8368-8372. Seo, J. S., Lee, K. W., Kim, T. K., Baek, I. S., Im, J. Y. and Han, P. L. (2011) Behavioral stress causes mitochondrial dysfunction via ABAD up-regulation and aggravates plaque pathology in the brain of a mouse model of Alzheimer disease. Free radical biology & medicine 50, 1526-1535. Sharma, A. K., Pavlova, S. T., Kim, J., Finkelstein, D., Hawco, N. J., Rath, N. P., Kim, J. and Mirica, L. M. (2012) Bifunctional compounds for controlling metal-mediated aggregation of the abeta42 peptide. Journal of the American Chemical Society 134, 6625-6636. Shibata, M., Yamada, S., Kumar, S. R., Calero, M., Bading, J., Frangione, B., Holtzman, D. M., Miller, C. A., Strickland, D. K., Ghiso, J. and Zlokovic, B. V. (2000) Clearance of Alzheimer's amyloid-ss(1-40) peptide from brain by LDL receptor-related protein-1 at the blood-brain barrier. The Journal of clinical investigation 106, 1489-1499. Simon, A. M., de Maturana, R. L., Ricobaraza, A., Escribano, L., Schiapparelli, L., Cuadrado-Tejedor, M., Perez-Mediavilla, A., Avila, J., Del Rio, J. and Frechilla, D. (2009) Early changes in hippocampal Eph receptors precede the onset of memory decline in mouse models of Alzheimer's disease. Journal of Alzheimer's disease : JAD 17, 773-786. Singh, I., Sagare, A. P., Coma, M., Perlmutter, D., Gelein, R., Bell, R. D., Deane, R. J., Zhong, E., Parisi, M., Ciszewski, J., Kasper, R. T. and Deane, R. (2013) Low levels of copper disrupt brain amyloid-beta homeostasis by altering its production and clearance. Proceedings of the National Academy of Sciences of the United States of America 110, 14771-14776. Small, D. H., Maksel, D., Kerr, M. L., Ng, J., Hou, X., Chu, C., Mehrani, H., Unabia, S., Azari, M. F., Loiacono, R., Aguilar, M. I. and Chebib, M. (2007) The beta-amyloid protein of Alzheimer's disease binds to membrane lipids but does not bind to the alpha7 nicotinic acetylcholine receptor. Journal of neurochemistry 101, 1527-1538. Smilansky, A., Dangoor, L., Nakdimon, I., Ben-Hail, D., Mizrachi, D. and Shoshan-Barmatz, V. (2015) The voltage-dependent anion channel 1 mediates amyloid beta toxicity and represents a potential target for Alzheimer's disease therapy. The Journal of biological chemistry. Smith, M. A., Harris, P. L., Sayre, L. M. and Perry, G. (1997) Iron accumulation in Alzheimer disease is a source of redox-generated free radicals. Proceedings of the National Academy of Sciences of the United States of America 94, 9866-9868. Sousa, J. C., Cardoso, I., Marques, F., Saraiva, M. J. and Palha, J. A. (2007) Transthyretin and Alzheimer's disease: where in the brain? Neurobiology of aging 28, 713-718. Squitti, R., Lupoi, D., Pasqualetti, P., Dal Forno, G., Vernieri, F., Chiovenda, P., Rossi, L., Cortesi, M., Cassetta, E. and Rossini, P. M. (2002) Elevation of serum copper levels in Alzheimer's disease. Neurology 59, 1153-1161. Stanyon, H. F. and Viles, J. H. (2012) Human serum albumin can regulate amyloid-beta peptide fiber growth in the brain interstitium: implications for Alzheimer disease. The Journal of biological chemistry 287, 28163-28168. Stein, T. D. and Johnson, J. A. (2002) Lack of neurodegeneration in transgenic mice overexpressing mutant amyloid precursor protein is associated with increased levels of transthyretin and the activation of cell survival pathways. The Journal of neuroscience : the official journal of the Society for Neuroscience 22, 7380-7388. Stevens, R. W., Elmendorf, D., Gourlay, M., Stroebel, E. and Gaafar, H. A. (1979) Application of fluoroimmunoassay to cerebrospinal fluid immunoglobulin G and albumin. Journal of clinical
Page 57 of 68
Ac ce pt e
d
M
an
us
cr
ip t
microbiology 10, 346-350. Strittmatter, W. J., Saunders, A. M., Schmechel, D., Pericak-Vance, M., Enghild, J., Salvesen, G. S. and Roses, A. D. (1993a) Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proceedings of the National Academy of Sciences of the United States of America 90, 1977-1981. Strittmatter, W. J., Weisgraber, K. H., Huang, D. Y., Dong, L. M., Salvesen, G. S., Pericak-Vance, M., Schmechel, D., Saunders, A. M., Goldgaber, D. and Roses, A. D. (1993b) Binding of human apolipoprotein E to synthetic amyloid beta peptide: isoform-specific effects and implications for lateonset Alzheimer disease. Proceedings of the National Academy of Sciences of the United States of America 90, 8098-8102. Strober, W., Murray, P. J., Kitani, A. and Watanabe, T. (2006) Signalling pathways and molecular interactions of NOD1 and NOD2. Nature reviews. Immunology 6, 9-20. Sturchler, E., Galichet, A., Weibel, M., Leclerc, E. and Heizmann, C. W. (2008) Site-specific blockade of RAGE-Vd prevents amyloid-beta oligomer neurotoxicity. The Journal of neuroscience : the official journal of the Society for Neuroscience 28, 5149-5158. Suen, D. F., Norris, K. L. and Youle, R. J. (2008) Mitochondrial dynamics and apoptosis. Genes & development 22, 1577-1590. Suh, S. W., Jensen, K. B., Jensen, M. S., Silva, D. S., Kesslak, P. J., Danscher, G. and Frederickson, C. J. (2000) Histochemically-reactive zinc in amyloid plaques, angiopathy, and degenerating neurons of Alzheimer's diseased brains. Brain research 852, 274-278. Sun, X. Y., Wei, Y. P., Xiong, Y., Wang, X. C., Xie, A. J., Wang, X. L., Yang, Y., Wang, Q., Lu, Y. M., Liu, R. and Wang, J. Z. (2012) Synaptic released zinc promotes tau hyperphosphorylation by inhibition of protein phosphatase 2A (PP2A). The Journal of biological chemistry 287, 11174-11182. Sutcliffe, J. G., Hedlund, P. B., Thomas, E. A., Bloom, F. E. and Hilbush, B. S. (2011) Peripheral reduction of beta-amyloid is sufficient to reduce brain beta-amyloid: implications for Alzheimer's disease. Journal of neuroscience research 89, 808-814. Suzuki, K., Miura, T. and Takeuchi, H. (2001) Inhibitory effect of copper(II) on zinc(II)-induced aggregation of amyloid beta-peptide. Biochemical and biophysical research communications 285, 991-996. Syken, J., Grandpre, T., Kanold, P. O. and Shatz, C. J. (2006) PirB restricts ocular-dominance plasticity in visual cortex. Science 313, 1795-1800. Taguchi, A., Blood, D. C., del Toro, G., Canet, A., Lee, D. C., Qu, W., Tanji, N., Lu, Y., Lalla, E., Fu, C., Hofmann, M. A., Kislinger, T., Ingram, M., Lu, A., Tanaka, H., Hori, O., Ogawa, S., Stern, D. M. and Schmidt, A. M. (2000) Blockade of RAGE-amphoterin signalling suppresses tumour growth and metastases. Nature 405, 354-360. Tahara, K., Kim, H. D., Jin, J. J., Maxwell, J. A., Li, L. and Fukuchi, K. (2006) Role of toll-like receptor signalling in Abeta uptake and clearance. Brain : a journal of neurology 129, 3006-3019. Takai, T. (2005) Paired immunoglobulin-like receptors and their MHC class I recognition. Immunology 115, 433-440. Takasu, M. A., Dalva, M. B., Zigmond, R. E. and Greenberg, M. E. (2002) Modulation of NMDA receptordependent calcium influx and gene expression through EphB receptors. Science 295, 491-495. Takuma, K., Fang, F., Zhang, W., Yan, S., Fukuzaki, E., Du, H., Sosunov, A., McKhann, G., Funatsu, Y., Nakamichi, N., Nagai, T., Mizoguchi, H., Ibi, D., Hori, O., Ogawa, S., Stern, D. M., Yamada, K. and Yan, S. S. (2009) RAGE-mediated signaling contributes to intraneuronal transport of amyloid-beta and neuronal dysfunction. Proceedings of the National Academy of Sciences of the United States of America 106, 20021-20026. Takuma, K., Yao, J., Huang, J., Xu, H., Chen, X., Luddy, J., Trillat, A. C., Stern, D. M., Arancio, O. and Yan, S. S. (2005) ABAD enhances Abeta-induced cell stress via mitochondrial dysfunction. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 19, 597-598. Talaga, P. and Quere, L. (2002) The plasma membrane: a target and hurdle for the development of anti-Abeta drugs? Current drug targets. CNS and neurological disorders 1, 567-574. Terzi, E., Holzemann, G. and Seelig, J. (1997) Interaction of Alzheimer beta-amyloid peptide(1-40) with lipid membranes. Biochemistry 36, 14845-14852. Tillement, L., Lecanu, L. and Papadopoulos, V. (2011) Alzheimer's disease: effects of beta-amyloid on mitochondria. Mitochondrion 11, 13-21. Tokuda, T., Calero, M., Matsubara, E., Vidal, R., Kumar, A., Permanne, B., Zlokovic, B., Smith, J. D., Ladu, M. J., Rostagno, A., Frangione, B. and Ghiso, J. (2000) Lipidation of apolipoprotein E influences its isoform-specific interaction with Alzheimer's amyloid beta peptides. The Biochemical journal 348 Pt 2, 359-365. Tooyama, I., Kawamata, T., Akiyama, H., Kimura, H., Moestrup, S. K., Gliemann, J., Matsuo, A. and McGeer, P.
Page 58 of 68
Ac ce pt e
d
M
an
us
cr
ip t
L. (1995) Subcellular localization of the low density lipoprotein receptor-related protein (alpha 2macroglobulin receptor) in human brain. Brain research 691, 235-238. Trouw, L. A., Nielsen, H. M., Minthon, L., Londos, E., Landberg, G., Veerhuis, R., Janciauskiene, S. and Blom, A. M. (2008) C4b-binding protein in Alzheimer's disease: binding to Abeta1-42 and to dead cells. Molecular immunology 45, 3649-3660. Tsigelny, I. F., Crews, L., Desplats, P., Shaked, G. M., Sharikov, Y., Mizuno, H., Spencer, B., Rockenstein, E., Trejo, M., Platoshyn, O., Yuan, J. X. and Masliah, E. (2008) Mechanisms of hybrid oligomer formation in the pathogenesis of combined Alzheimer's and Parkinson's diseases. PloS one 3, e3135. Udan, M. L., Ajit, D., Crouse, N. R. and Nichols, M. R. (2008) Toll-like receptors 2 and 4 mediate Abeta(1-42) activation of the innate immune response in a human monocytic cell line. Journal of neurochemistry 104, 524-533. Um, J. W., Nygaard, H. B., Heiss, J. K., Kostylev, M. A., Stagi, M., Vortmeyer, A., Wisniewski, T., Gunther, E. C. and Strittmatter, S. M. (2012) Alzheimer amyloid-beta oligomer bound to postsynaptic prion protein activates Fyn to impair neurons. Nature neuroscience 15, 1227-1235. Vazzana, N., Santilli, F., Cuccurullo, C. and Davi, G. (2009) Soluble forms of RAGE in internal medicine. Internal and emergency medicine 4, 389-401. Velayudhan, L., Killick, R., Hye, A., Kinsey, A., Guntert, A., Lynham, S., Ward, M., Leung, R., Lourdusamy, A., To, A. W., Powell, J. and Lovestone, S. (2012) Plasma transthyretin as a candidate marker for Alzheimer's disease. Journal of Alzheimer's disease : JAD 28, 369-375. Venkitaramani, D. V., Chin, J., Netzer, W. J., Gouras, G. K., Lesne, S., Malinow, R. and Lombroso, P. J. (2007) Beta-amyloid modulation of synaptic transmission and plasticity. The Journal of neuroscience : the official journal of the Society for Neuroscience 27, 11832-11837. Verdier, Y., Zarandi, M. and Penke, B. (2004) Amyloid beta-peptide interactions with neuronal and glial cell plasma membrane: binding sites and implications for Alzheimer's disease. Journal of peptide science : an official publication of the European Peptide Society 10, 229-248. von Ballmoos, C., Wiedenmann, A. and Dimroth, P. (2009) Essentials for ATP synthesis by F1F0 ATP synthases. Annual review of biochemistry 78, 649-672. Walker, D. G. and Lue, L. F. (2005) Investigations with cultured human microglia on pathogenic mechanisms of Alzheimer's disease and other neurodegenerative diseases. Journal of neuroscience research 81, 412425. Walter, S., Letiembre, M., Liu, Y., Heine, H., Penke, B., Hao, W., Bode, B., Manietta, N., Walter, J., SchulzSchuffer, W. and Fassbender, K. (2007) Role of the toll-like receptor 4 in neuroinflammation in Alzheimer's disease. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 20, 947-956. Wang, H. Y., Lee, D. H., D'Andrea, M. R., Peterson, P. A., Shank, R. P. and Reitz, A. B. (2000a) betaAmyloid(1-42) binds to alpha7 nicotinic acetylcholine receptor with high affinity. Implications for Alzheimer's disease pathology. The Journal of biological chemistry 275, 5626-5632. Wang, H. Y., Lee, D. H., Davis, C. B. and Shank, R. P. (2000b) Amyloid peptide Abeta(1-42) binds selectively and with picomolar affinity to alpha7 nicotinic acetylcholine receptors. Journal of neurochemistry 75, 1155-1161. Wang, H. Y., Li, W., Benedetti, N. J. and Lee, D. H. (2003) Alpha 7 nicotinic acetylcholine receptors mediate beta-amyloid peptide-induced tau protein phosphorylation. The Journal of biological chemistry 278, 31547-31553. Wang, H. Y., Stucky, A., Liu, J., Shen, C., Trocme-Thibierge, C. and Morain, P. (2009a) Dissociating betaamyloid from alpha 7 nicotinic acetylcholine receptor by a novel therapeutic agent, S 24795, normalizes alpha 7 nicotinic acetylcholine and NMDA receptor function in Alzheimer's disease brain. The Journal of neuroscience : the official journal of the Society for Neuroscience 29, 10961-10973. Wang, X., Su, B., Lee, H. G., Li, X., Perry, G., Smith, M. A. and Zhu, X. (2009b) Impaired balance of mitochondrial fission and fusion in Alzheimer's disease. The Journal of neuroscience : the official journal of the Society for Neuroscience 29, 9090-9103. Wang, X., Su, B., Siedlak, S. L., Moreira, P. I., Fujioka, H., Wang, Y., Casadesus, G. and Zhu, X. (2008) Amyloid-beta overproduction causes abnormal mitochondrial dynamics via differential modulation of mitochondrial fission/fusion proteins. Proceedings of the National Academy of Sciences of the United States of America 105, 19318-19323. Waschuk, S. A., Elton, E. A., Darabie, A. A., Fraser, P. E. and McLaurin, J. A. (2001) Cellular membrane composition defines A beta-lipid interactions. The Journal of biological chemistry 276, 33561-33568. Wati, H., Kawarabayashi, T., Matsubara, E., Kasai, A., Hirasawa, T., Kubota, T., Harigaya, Y., Shoji, M. and Maeda, S. (2009) Transthyretin accelerates vascular Abeta deposition in a mouse model of Alzheimer's disease. Brain pathology 19, 48-57.
Page 59 of 68
Ac ce pt e
d
M
an
us
cr
ip t
Webster, S. and Rogers, J. (1996) Relative efficacies of amyloid beta peptide (A beta) binding proteins in A beta aggregation. Journal of neuroscience research 46, 58-66. Wilhelmus, M. M., Otte-Holler, I., Wesseling, P., de Waal, R. M., Boelens, W. C. and Verbeek, M. M. (2006) Specific association of small heat shock proteins with the pathological hallmarks of Alzheimer's disease brains. Neuropathology and applied neurobiology 32, 119-130. Wilson, L. M., Pham, C. L., Jenkins, A. J., Wade, J. D., Hill, A. F., Perugini, M. A. and Howlett, G. J. (2006) High density lipoproteins bind Abeta and apolipoprotein C-II amyloid fibrils. Journal of lipid research 47, 755-760. Wisniewski, T., Castano, E. M., Golabek, A., Vogel, T. and Frangione, B. (1994) Acceleration of Alzheimer's fibril formation by apolipoprotein E in vitro. The American journal of pathology 145, 1030-1035. Wolf, B. B., Lopes, M. B., VandenBerg, S. R. and Gonias, S. L. (1992) Characterization and immunohistochemical localization of alpha 2-macroglobulin receptor (low-density lipoprotein receptorrelated protein) in human brain. The American journal of pathology 141, 37-42. Wood, S. J., Chan, W. and Wetzel, R. (1996) Seeding of A beta fibril formation is inhibited by all three isotypes of apolipoprotein E. Biochemistry 35, 12623-12628. Xie, L., Helmerhorst, E., Taddei, K., Plewright, B., Van Bronswijk, W. and Martins, R. (2002) Alzheimer's betaamyloid peptides compete for insulin binding to the insulin receptor. The Journal of neuroscience : the official journal of the Society for Neuroscience 22, RC221. Xiong, Y., Jing, X. P., Zhou, X. W., Wang, X. L., Yang, Y., Sun, X. Y., Qiu, M., Cao, F. Y., Lu, Y. M., Liu, R. and Wang, J. Z. (2013) Zinc induces protein phosphatase 2A inactivation and tau hyperphosphorylation through Src dependent PP2A (tyrosine 307) phosphorylation. Neurobiology of aging 34, 745-756. Yaar, M., Zhai, S., Pilch, P. F., Doyle, S. M., Eisenhauer, P. B., Fine, R. E. and Gilchrest, B. A. (1997) Binding of beta-amyloid to the p75 neurotrophin receptor induces apoptosis. A possible mechanism for Alzheimer's disease. The Journal of clinical investigation 100, 2333-2340. Yamada, K., Hashimoto, T., Yabuki, C., Nagae, Y., Tachikawa, M., Strickland, D. K., Liu, Q., Bu, G., Basak, J. M., Holtzman, D. M., Ohtsuki, S., Terasaki, T. and Iwatsubo, T. (2008) The low density lipoprotein receptor-related protein 1 mediates uptake of amyloid beta peptides in an in vitro model of the bloodbrain barrier cells. The Journal of biological chemistry 283, 34554-34562. Yamamoto, K., Shimada, H., Koh, H., Ataka, S. and Miki, T. (2013) Serum levels of albumin-amyloid beta complexes are decreased in Alzheimer's disease. Geriatrics & gerontology international. Yamamoto, T., Yamada, A., Watanabe, M., Yoshimura, Y., Yamazaki, N., Yoshimura, Y., Yamauchi, T., Kataoka, M., Nagata, T., Terada, H. and Shinohara, Y. (2006) VDAC1, having a shorter N-terminus than VDAC2 but showing the same migration in an SDS-polyacrylamide gel, is the predominant form expressed in mitochondria of various tissues. Journal of proteome research 5, 3336-3344. Yamauchi, K., Tozuka, M., Hidaka, H., Nakabayashi, T., Sugano, M., Kondo, Y., Nakagawara, A. and Katsuyama, T. (2000) Effect of apolipoprotein AII on the interaction of apolipoprotein E with betaamyloid: some apo(E-AII) complexes inhibit the internalization of beta-amyloid in cultures of neuroblastoma cells. Journal of neuroscience research 62, 608-614. Yan, S. D., Chen, X., Fu, J., Chen, M., Zhu, H., Roher, A., Slattery, T., Zhao, L., Nagashima, M., Morser, J., Migheli, A., Nawroth, P., Stern, D. and Schmidt, A. M. (1996) RAGE and amyloid-beta peptide neurotoxicity in Alzheimer's disease. Nature 382, 685-691. Yan, S. D., Fu, J., Soto, C., Chen, X., Zhu, H., Al-Mohanna, F., Collison, K., Zhu, A., Stern, E., Saido, T., Tohyama, M., Ogawa, S., Roher, A. and Stern, D. (1997) An intracellular protein that binds amyloidbeta peptide and mediates neurotoxicity in Alzheimer's disease. Nature 389, 689-695. Yan, S. D., Stern, D., Kane, M. D., Kuo, Y. M., Lampert, H. C. and Roher, A. E. (1998) RAGE-Abeta interactions in the pathophysiology of Alzheimer's disease. Restorative neurology and neuroscience 12, 167-173. Yan, S. D., Zhu, H., Zhu, A., Golabek, A., Du, H., Roher, A., Yu, J., Soto, C., Schmidt, A. M., Stern, D. and Kindy, M. (2000) Receptor-dependent cell stress and amyloid accumulation in systemic amyloidosis. Nature medicine 6, 643-651. Yan, Y. and Wang, C. (2007) Abeta40 protects non-toxic Abeta42 monomer from aggregation. Journal of molecular biology 369, 909-916. Yang, D. S., Smith, J. D., Zhou, Z., Gandy, S. E. and Martins, R. N. (1997) Characterization of the binding of amyloid-beta peptide to cell culture-derived native apolipoprotein E2, E3, and E4 isoforms and to isoforms from human plasma. Journal of neurochemistry 68, 721-725. Yao, J., Du, H., Yan, S., Fang, F., Wang, C., Lue, L. F., Guo, L., Chen, D., Stern, D. M., Gunn Moore, F. J., Xi Chen, J., Arancio, O. and Yan, S. S. (2011) Inhibition of amyloid-beta (Abeta) peptide-binding alcohol dehydrogenase-Abeta interaction reduces Abeta accumulation and improves mitochondrial function in a mouse model of Alzheimer's disease. The Journal of neuroscience : the official journal of the Society
Page 60 of 68
Ac ce pt e
d
M
an
us
cr
ip t
for Neuroscience 31, 2313-2320. Yazawa, H., Yu, Z. X., Takeda, Le, Y., Gong, W., Ferrans, V. J., Oppenheim, J. J., Li, C. C. and Wang, J. M. (2001) Beta amyloid peptide (Abeta42) is internalized via the G-protein-coupled receptor FPRL1 and forms fibrillar aggregates in macrophages. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 15, 2454-2462. Ye, S., Huang, Y., Mullendorff, K., Dong, L., Giedt, G., Meng, E. C., Cohen, F. E., Kuntz, I. D., Weisgraber, K. H. and Mahley, R. W. (2005) Apolipoprotein (apo) E4 enhances amyloid beta peptide production in cultured neuronal cells: apoE structure as a potential therapeutic target. Proceedings of the National Academy of Sciences of the United States of America 102, 18700-18705. Yoshiike, Y., Tanemura, K., Murayama, O., Akagi, T., Murayama, M., Sato, S., Sun, X., Tanaka, N. and Takashima, A. (2001) New insights on how metals disrupt amyloid beta-aggregation and their effects on amyloid-beta cytotoxicity. The Journal of biological chemistry 276, 32293-32299. Zabel, M., Schrag, M., Mueller, C., Zhou, W., Crofton, A., Petersen, F., Dickson, A. and Kirsch, W. M. (2012) Assessing candidate serum biomarkers for Alzheimer's disease: a longitudinal study. Journal of Alzheimer's disease : JAD 30, 311-321. Zatta, P., Bordin, C. and Favarato, M. (1993) The inhibition of trypsin and alpha-chymotrypsin proteolytic activity by aluminum(III). Archives of biochemistry and biophysics 303, 407-411. Zerbinatti, C. V. and Bu, G. (2005) LRP and Alzheimer's disease. Reviews in the neurosciences 16, 123-135. Zerbinatti, C. V., Wahrle, S. E., Kim, H., Cam, J. A., Bales, K., Paul, S. M., Holtzman, D. M. and Bu, G. (2006) Apolipoprotein E and low density lipoprotein receptor-related protein facilitate intraneuronal Abeta42 accumulation in amyloid model mice. The Journal of biological chemistry 281, 36180-36186. Zerbinatti, C. V., Wozniak, D. F., Cirrito, J., Cam, J. A., Osaka, H., Bales, K. R., Zhuo, M., Paul, S. M., Holtzman, D. M. and Bu, G. (2004) Increased soluble amyloid-beta peptide and memory deficits in amyloid model mice overexpressing the low-density lipoprotein receptor-related protein. Proceedings of the National Academy of Sciences of the United States of America 101, 1075-1080. Zhang, W., Wang, L. Z., Yu, J. T., Chi, Z. F. and Tan, L. (2012) Increased expressions of TLR2 and TLR4 on peripheral blood mononuclear cells from patients with Alzheimer's disease. Journal of the neurological sciences 315, 67-71. Zou, K., Gong, J. S., Yanagisawa, K. and Michikawa, M. (2002) A novel function of monomeric amyloid betaprotein serving as an antioxidant molecule against metal-induced oxidative damage. The Journal of neuroscience : the official journal of the Society for Neuroscience 22, 4833-4841.
Page 61 of 68
Table 1. Clinical trials targeting A-interacting molecules Table 1. Clinical trials targeting A-interacting molecules
Instituto Grifols, S.A Albumin
Instituto Grifols, S.A
RAGE
ApoE
Characterisitics A Study to Evaluate Albumin and Immunoglobulin in Alzheimer's Disease (AMBAR) Efficacy and Safety of Plasma Exchange With 5% Albutein in Beta-Amyloid Peptide Clearance in Cerebrospinal Fluid
Status
NCT number
Pfizer & Alzheimer's Disease A Phase 2 Study Evaluating The Efficacy And Safety Of Cooperative Study (ADCS) PF 04494700 In Mild To Moderate Alzheimer's Disease
Phase ൖ (Completed)
NCT00742417
Phase ൖ (Completed)
NCT00566397
MN Sabbagh et al (Alzheimer Dis Assoc Disord. 2011), Galasko D et al (Neurology. 2014)
vTv Therapeutics
Evaluation of the Efficacy and Safety of TTP488 in Patients With Mild Alzheimer's Disease
Phase ൗ (Recruiting)
NCT02080364
AH Burstein et al (BMC Neurol. 2014)
The Cleveland Clinic
Bexarotene Amyloid Treatment for Alzheimer's Disease (BEAT-AD)
Phase ൖ (Completed)
NCT01782742
Dai W et al (Neurodegener Dis. 2014), Aicardi G et al (Rejuvenation Res. 2013), etc.
NCT00608946
TA Bayer et al (Proc Natl Acad Sci USA. 2003), H Kessler et al (J Neural Transm. 2008)
Copper, Zinc
us
University Hospital, Saarland & Treatment With Copper in Patients With Mild Alzheimer´s Phase ൖ (Completed) University of Goettingen Dementia
Adeona Pharmaceuticals
Trial of Novel Oral Zinc Cysteine Preparation in Alzheimer's Disease
Prana Biotechnology Limited
Study Evaluating the Safety, Tolerability and Efficacy of PBT2 in Patients With Early Alzheimer's Disease
Phase ൖ (Completed)
NCT00471211
L Lannfelt et al (Lancet Neurol. 2008)
AbbVie
Evaluate the Efficacy and Safety of ABT-126 in Subjects Phase ൖ (Completed) with Mild to Moderate Alzheimer's Disease
NCT00948909
LM Gault et al (Alzheimers Dement. 2015)
an
Unknown
NCT01099332
M
7- nAchR
Relevant Publications
Phase ൖ & ൗ trial (Recruiting) NCT01561053
ip t
Company/Sponsors
cr
Molecules
Ac ce pt e
d
Data obtained from www.clinicaltrials.gov
Page 62 of 68
Ac ce pt e
d
M
an
us
cr
ip t
Figure 1. Diverse A-interacti A ing moleculles in differeent regions of body com mpartmentss
Abbrevviations: SA AP, serum amyloid a P componentt; ApoE, Apolipoprote A ein E; HDL L, highdensity lipoproteinn; RAGE, receptor r forr advanced d glycation end-produccts; TLR2, toll-like n; PrP, prion n protein; Ep EphB2, Ephrrin typereceptorr 2; LRP, lipoprotein receptor-relaated protein B recepptor 2; AP PP, amyloid precursoor protein; NMDA, N-methyl-D N D-aspartate; ERAB, endoplaasmic reticuulum-associiated amylooid beta; Ap poJ, Apolip poprotein J;; LilrB2, leeukocyte immunooglobulin-liike recepto or subfamilly B; 7nA AChR, alph ha-7 nicotinnic recepto or; SEC receptorr, serpin-ennzyme comp plex receptoor; p75NTR R, p75 neurotrophin receeptor
Page 63 of 68
Ac ce pt e
d
M
an
us
cr
ip t
Figure 22. A-binding membraane receptorrs in neuron and microg glia.
Abbrevviations: SEC receptor, serpin-enzzyme compllex receptorr; PirB, pairred Ig-like receptor B; p75N NTR, p75 neurotrophi n in receptor;; PrP, prion n protein; NMDA, N N-m methyl-D-asspartate; EphB2,, Ephrin typpe-B recepto or 2; 7nAC ChR, alpha--7 nicotinic acetylcholiine receptorr; RAGE, receptorr for advannced glycattion end-prooducts; TL LR2, toll-lik ke receptor 2; JNK, c-Jun c Nterminaal kinase; p38-MAPK, p , p38-mitoggen-activateed protein kinase; k NF--B, nucleaar factor kappa B B; PI3K, phhosphoinosittide 3-kinasse; ERK, ex xtracellular signal-regul s lated kinasees; PKC, protein kinase C; PYK2, P calciium sensitivve tyrosine kinase k 2
Page 64 of 68
Ac ce pt e
d
M
an
us
cr
ip t
Figure 33. Mitochonndrial A-biinding compponents
Abbrevviations: TO OM, translo ocase of thhe outer membrane; m ABAD, A A binding alcohol dehydroogenase; AN NT, adenine nucleotidde translocaator; hPreP, human preesequence protease; p VDAC,, voltage-deependent an nion channnel; Fis1, fission f proteein 1; Drp 1, dynamin n-related protein 1
Page 65 of 68
Abbreviation list.
AD: Alzheimer’s Disease A: amyloid beta
ip t
ADAS-Cog : Alzheimer’s Disease Assessment Scale-cognitive subscale MMSE: Mini-Mental State Examination
cr
ApoE: Apolipoprotein E
us
APP: amyloid precursor protein BBB: blood brain barrier
an
RXR: retinoid X receptor
PPAR: peroxisome proliferator-activated receptor gamma
M
LXR: liver X receptor ApoJ: apolipoprotein J
Ac ce pt e
HDL: high density lipoproteins
d
LRP: low-density lipoprotein receptor-related protein
SAP: serum amyloid P component PP2A: protein phosphatase 2A
RAGE: receptor for advanced glycation end products ERK: extracellular signal-related kinases NF-B: nuclear factor kappa B MMP: matrix metalloprotease
NMDA: N-methyl-D-aspartate
p75NTR: the 75-kD neurotrophin receptor TrkA: tyrosine kinase receptor A SEC receptor: serpin-enzyme complex receptor 7nAChR: 7 nicotinic acetylcholine receptor
Page 66 of 68
MAPK: mitogen-activated protein kinase PI3-k: phosphatidylinositol 3-kinase EphB2: ephrin type-B receptor 2 PrP: prion protein
ERAB: endoplasmic reticulum-associated A peptide binding protein
cr
PTB domain: phosphotyrosin-binding domain
mPTP: mitochondrial permeability transition pore
an
ABAD: A-binding alcohol dehydrogenase VDAC: voltage-dependent anion channel
d
Ac ce pt e
Drp1: dynamin related protein 1
M
ANT: adenine nucleotide translocase
hPreP: presequence protease
us
Hsp: heat shock protein
TOM: translocase of the outer membrane
ip t
LilrB2(PriB): leukocyte immunoglobulin-like receptor B2
Fis 1: fission protein 1
PreP: presequence protease TLR: toll-like receptor
MAP3K: mitogen-activated protein 3 kinases JNK: c-Jun N-terminal kinases
mFPR2: mouse G-protein coupled formyl peptide receptor M-CSF: macrophage-colony stimulating factor CAA: cerebral amyloid angiopathy PKC: protein kinase C PYK2: calcium sensitive tyrosine kinase SR: scavenger receptor
Page 67 of 68
Highlights
z A-interacting proteins in the blood and brain
z Intracellular A-binding proteins z Mitochondrial A-binding components
us
z A-interacting mediators of immune activation
cr
z A-binding membrane components (receptors)
ip t
z A-interacting metal ions
Ac ce pt e
d
M
an
z Other amyloidogenic proteins
Page 68 of 68