Rotational study of the bimolecule acetic acid-fluoroacetic acid

Rev. Neurosci. 2014; 25(6): 773–783

Luis Fernando Hernández-Zimbrón* and Selva Rivas-Arancibia

Deciphering an interplay of proteins associated with amyloid β 1-42 peptide and molecular mechanisms of Alzheimer’s disease Abstract: Extracellular and intracellular accumulation of amyloid beta 1-42 peptide in different states of aggregation has been involved in the development and progression of Alzheimer’s disease. However, the precise mechanisms involved in amyloid beta peptide neurotoxicity have not been fully understood. There exists a wide variety of studies demonstrating the binding of amyloid beta peptide to a great variety of macromolecules and that such associations affect the cellular functions. This type of association involves proteins and receptors anchored to the plasma membrane of neurons or immune cells of the central nervous system as well as intracellular proteins that can alter intracellular transport, activate signaling pathways or affect proper mitochondrial function. In this review, we present some examples of such associations and the role played by these interactions, which are generally involved in the pathological progression of Alzheimer’s disease. Keywords: Alzheimer’s disease; amyloid beta; protein interactions. DOI 10.1515/revneuro-2014-0025 Received March 21, 2014; accepted June 1, 2014; previously published online July 10, 2014

Introduction Alzheimer’s disease (AD) is a paradigm of a neurodegenerative disorder that is caused by detrimental progression of age-dependent loss of cognitive function. The hallmarks of this disease are conglomeration of amyloid aggregates (also known as amyloid plaques) in the extracellular brain parenchyma as well as the formation of neurofibrillary *Corresponding author: Luis Fernando Hernández-Zimbrón, Faculty of Medicine, Physiology Department, National Autonomous University of Mexico, CP 04510, Mexico City, Mexico, e-mail: [email protected] Selva Rivas-Arancibia: Faculty of Medicine, Physiology Department, National Autonomous University of Mexico, CP 04510, Mexico City, Mexico

tangles within the neurons. Amyloid plaques are spherical lesions of approximately 200 μm constituted mainly by local deposits of extracellular amyloid β peptide of approximately 4 kDa, having a length of 39–43 amino acids (Small and McLean, 1999). Neurofibrillary tangles are abnormal intracellular filaments that displace the cytoplasmic organelles. Such tangles or aggregates are found in the hippocampal pyramidal cells as well as in the basalis nuclei. In the hippocampus, persistent tangles were observed even after cell death. These neurofibrillary tangles consist of cross-linked protein strands generating a double helix structure. The principal component of these tangles is the pathologically hyper phosphorylated Tau protein (Gouras et al., 2000).

Origin of βA peptide: an enzymatic inception The βA peptide is derived from an altered processing of amyloid precursor protein (APP). APP is a type I transmembrane protein and has been reported to be expressed in three isoforms (APP695, APP751 and APP770) (Selkoe, 2001; Smith, 2007). There are two pathways of APP enzymatic processing, amyloidogenic and non-amyloidogenic.

Amyloidogenic pathway The amino-terminus of APP is cleaved by β-secretase, whereas the APP C-terminus is cleaved by γ-secretase, thus representing the amyloidogenic pathway of APP processing. β-Secretase cleaves APP between residues Met671 and Asp672, giving rise to a soluble peptide of APP (βAPPs) and the C99 fragment. The γ-secretase cleavage site occurs in the vicinity of residue 712 of the C-terminus; γ-secretase can cleave the C-terminus region in Val711 or IIe 713 to produce the short peptide βA (βA40) or the long peptide (βA42). In addition to the βA peptide, a C-terminal peptide of approximately 50 residues of APP is also released, which is also known as the APP intracellular domain (AICD) (Figure 1).

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774      L.F. Hernández-Zimbrón and S. Rivas-Arancibia: Deciphering an interplay of proteins associated with amyloid β 1-42 peptide

Figure 1 Non-amyloidogenic and amyloidogenic pathways of APP. In the amyloidogenic pathway, monomers of βA 1-42 and βA 1-40 peptide are derived from APP and form aggregates of different molecular weights that lead to amyloid plaques, which are the hallmark of AD. APP protein is a substrate for enzymatic cleavage by β secretase (BACE), which releases sAPPB and the C99 fragment within the membrane. Then, the C99 fragment is cleaved by the γ-secretase complex formed by presenilin 1 or 2 and nicastrin. The activity of the amyloidogenic pathway and the membrane damage caused by peptide Aβ 1-42 increase in areas associated with lipid rafts. In the non-amyloidogenic pathway, the cleavage by alpha-secretase occurs within the Aβ region, the C83 peptide is cut by γ-secretase, and the peptide P3 fragment is then produced, which precludes Aβ formation (modified from La Ferla et al., 2007).

Non-amyloidogenic pathway APP can also be processed by α-secretase (TACE), which cuts the βAPPs fragment between Lys687 and Leu 688, thus producing a long soluble domain. Likewise the C-terminal fragment containing P3 and the C83 domain is formed by α-secretase at residue 711 or 713 to release the P3 fragment. This non-amyloidogenic pathway does not produce the βA peptide (Figure 1).

Interaction of βA 1-42 peptide with other proteins βA peptide is found in the brain and circulating blood of patients suffering AD. However, in patients with AD, there are a large amount of amyloid oligomers and aggregates that are associated with neurodegeneration. Ample evidence has emerged suggesting that βA aggregation to form soluble oligomers or fibrils is an important mechanism for

the development of its toxic effects (Pike et  al., 1991; Koo et al., 1999; Selkoe, 1999). One major damage caused by the βA peptide is the malfunction of various proteins. Recently, there have been several studies showing that βA peptide interacts with a wide variety of cell surface proteins, as well as intracellular proteins, and has the capacity to induce cell death as a result of such associations. In this review, we will emphasize the most recent studies that have shown interaction of βA 1-42 peptide with membrane-associated and intracellular proteins of neuronal cells and consortia of immune system cells, highlighting the biological significance of these interactions.

Association of βA 1-42 peptide with receptors and membrane proteins in neurons and glia The tethering of βA 1-42 to membrane has been extensively studied to understand its toxic effects in neurons

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L.F. Hernández-Zimbrón and S. Rivas-Arancibia: Deciphering an interplay of proteins associated with amyloid β 1-42 peptide      775

as well as the microglia activation mechanisms involved in local inflammation. One of the major binding sites for βA 1-42 is lipid membranes, which have very high binding energy resulting from the interaction of βA 1-42 hydrophobic domains with the membrane (Khan et  al., 2010). However, intriguing studies have proposed that the intracellular accumulation of βA 1-42 can be detected before its adherence to the membrane and formation of extracellular deposits. The most recent findings about membrane proteins binding to βA 1-42 are explained in detail below. The alpha-nicotinic alpha 7 receptor (α7 nAChR) is an integral membrane protein with a pentameric structure. This receptor is activated upon the binding of acetylcholine through a conformational change that affects the five subunits and causes the opening of a cation channel through the plasma membrane (Peng et al., 1994; Talaga and Quere, 2002). This receptor is expressed primarily on structures of the frontal brain regions whose neurons project towards the cortex and hippocampus. These specific areas are usually associated with the amyloid aggregates in AD. One of the main functions of this receptor is to modulate calcium homeostasis and the liberation of acetylcholine in processes involved learning and memory. Several studies have shown that α7 nAChR is co-localized with βA 1-42 neurons and neuritic plaques in AD. In this interaction, the sequence 12–28 within the βA 1-42 is responsible for this high affinity interaction (Wang et al., 2000). It has also been determined that the presence of intracellular or extracellular βA 1-42 (and not βA 1-40) attenuates the dependent response of this receptor in an irreversible manner (Liu et al., 2001; Dineley et al., 2002; Lee and Wang, 2003). Two important aspects of this interaction are as follows: 1) High-affinity binding between the receptor and the βA 1-42 in the plasma membrane. This association facilitates the internalization of amyloid peptide and causes endocytosis of the resulting complex. 2) The internalization of βA participates in the rapid and irreversible phosphorylation of Tau, a distinctive feature in AD (Wang et al., 2003). This mechanism is activated through signaling pathways regulated by extracellular kinase and c-jun kinase (Scheff et al., 2007; Wang et al., 2009). Moreover, it was found that the Aβ 1-42 peptide inhibits the calciumdependent endocytosis of α7 nAChR in synaptosomes (Puzzo et al., 2008; Dziewczapolski et al., 2009), and this interaction participates in the mechanisms of long-term potentiation (LTP). Puzo and colleagues showed that picomolar concentrations of βA 1-42 peptide lead to a stimulatory effect on hippocampal LTP mediated by presynaptic nAChR, whereas nanomolar concentrations produced an inhibitory effect, demonstrating that the stimulatory or inhibitory effects are concentration dependent.

Additionally, it has been reported (Oz et al., 2013) that Aβ 1-42 stimulated presynaptic calcium levels due to its association with exogenously expressed α7 nAChRs in axonal varicosities using the presynaptic model system of neuroblastoma hybrid cells NG 108-15. These responses were concentration dependent and sensitive to the specific antagonist of this receptor (α-bungarotoxin). Furthermore, after receptor activation and the increase of presynaptic calcium stimulated by βA 1-42, the calcium channels are opened by voltage-gated pumps while calcium reservoirs also participate in the increase of calcium. Furthermore, the membrane regions known as lipid rafts are important for stimulatory effects caused by βA 1-42 because disruption of these structures eliminates cholesterol, thus attenuating the receptor activation and the increased presynaptic calcium levels caused by amyloid beta peptide 1-42. The responses to nicotine remained intact, suggesting that the nicotinic receptor complex participates as a target for βA 1-42 agonist effects at picomolar and nanomolar concentrations in the pre-synaptic nerve terminal, including the possible involvement of lipid rafts associated with this receptor. According to the authors, the results suggest that this interaction plays a major role as a neuromodulator in synaptic mechanisms. In relation with these mechanisms, also we want to discuss the relevance of the interaction between Aβ 1-42 and acetilcholinesterase (AchE) enzyme. AchE best known for hydrolyzing the neurotransmitter acetylcholine, is also found in the amyloid plaques in the brains of Alzheimer’s patients and AChE inhibitors drugs have been used, which seem to offer any specific benefit to these patients. Several years ago, Inestrosa and collaborators, showed thah AChE is a potent amyloid promoting factor when compared with other Aβ-associated proteins. In this case it is necessary to mention that they used Aβ 1-40 in the in vitro experiments and the monomeric form of AChE was more prone to induce amyloid fibril formation (Inestrosa et al., 1996). More recently, Ress T. using transgenic mice (Tg2576 mice, which express human amyloid precursor protein and develop plaques at 9 months, with transgenic mice expressing human AChE) showed that the plaque numbers increased with age and plaques remained more numerous in the doubly transgenic animals at 9 and 12 months (Rees et al., 2003). Then, the histological and biochemical results support the conclusion that the interaction between AChE and amyloid beta 1-42 may play a role in pathogenesis of Alzheimer’s disease. Another receptor affected by the beta amyloid 1-42 peptide is the P75 neurotrophin receptor (p75NTR). This is a non-selective neurotrophin receptor that belongs to the family of cell death receptors (Kuner et al., 1998). This

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776      L.F. Hernández-Zimbrón and S. Rivas-Arancibia: Deciphering an interplay of proteins associated with amyloid β 1-42 peptide receptor can be activated by nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin-3 and neurotrophin-4. This receptor and its ligands mediate the survival and death of neurons. The p75NTR structure corresponds to a type I transmembrane protein that is Nand O-glycosylated. Some characteristics of this protein are a) high expression in cholinergic neurons of the basal nuclear complex, b) sensitivity to the toxicity of βA and c)  structural changes in AD (Geula, 1998). To date, two forms of p75NTR are known, monomeric and trimeric (Yaar et al., 1997). The trimeric form joins to βA, inducing receptor activation (Bothwell, 1996). The interaction of fibrillar βA 1-42 (fβA1-42) with p75NTR activates apoptosis. This mechanism of cell death involves the activation of nuclear factor kappa B (NFκB) in a time-dose dependent manner. Yaar and collaborators showed that prohibiting this interaction inhibits the activation of NFκB, thus attenuating the apoptotic process induced by βA 1-42. The above data suggest that this interaction is closely related to neuronal loss in AD (Yaar et al., 2002). Another example of Aβ-protein interaction has been recently described with Brain-derived Neurotrophic Factor Receptor (BDNF-R) and is directly related to the canonical Nerve Growth Factor (NGF) signaling pathway. In this case, βA1-42 peptide oligomers bind to BDNF-R and suppress the expression levels of BDNF and NGF. Artificial treatment with BDNF in rodents and non-human primates increased the neuronal survival and synaptic function and improved memory (Garzon and Fahnestock, 2007). Nagahara and colleagues (Nagahara et  al., 2009) demonstrated in animal models of AD that the administration and induction of endogenous expression of BDNF could function as an alternative AD treatment (Ernfors and Bramham, 2003). Finally, some results suggest that soluble Aβ assemblies cause synaptic dysfunction by disrupting both neurotransmitter and neurotrophin signaling (Poon et al., 2011). Transmembrane APP protein is expressed constitutively and is mainly found in the synapses of neurons. Its primary function is unknown, but it has been implicated as a physiological regulator in synapses (Panegyres, 2001) and, as previously mentioned, participates as a precursor of amyloid beta peptide in AD (Morris et  al., 2003). Through the use of co-immunoprecipitation, membrane proteins were purified that associated with fibrillar βA1-40 and βA1-42. In this manner, the βA1-42 peptide interacts with transmembrane APP and the soluble forms of APP, suggesting that fβA1-42 can bind to the cytosolic carboxyl terminal fragment (Lorenzo et al., 2000). Moreover, studies using APP knockout neurons showed that there is a reduction in vulnerability to

neurotoxicity caused by amyloid beta peptide, suggesting that the interaction between APP and βA1-42 participates in peptide neurotoxicity. This suggests that the binding of βA to APP increases cell toxicity, possibly by inducing a conformational change in APP, which could trigger cell death. Alzheimer’s disease is usually characterized as a disorder due to synaptic failure. Thinking about this, an interaction between the N-methyl-D-aspartate receptor (NMDAR) and beta amyloid peptide could be crucial in synaptic failure. This receptor is a glutamate receptor characterized by a high affinity to NMDA, is associated with a calcium channel of high conductance and is blocked by magnesium (Mg2+) under non-depolarizing conditions in a voltage-dependent manner (Dunah et al., 2000). The function of these receptors and synapse maturation involving the NMDAR is regulated by proteins called integrins (Chavis and Westbrook, 2001; Lin et  al., 2003). Changes in the release of presynaptic neurotransmitters and in postsynaptic ionic currents of glutamate receptors occur partly as a result of endocytosis of NMDAR as well as of the surface receptor propionic acid α-amino3-hydroxy-5-methyl-4-isoxazole (AMPAR). These changes weaken synaptic activity due to the reduction in synaptic currents after a train of high frequency stimulator. Intracellular βA-42 can enhance these synaptic deficits at a younger age (Mucke et  al., 2000). These changes in the activity of receptors and, therefore, the synaptic dynamics are caused by the interaction of NMDA and AMPA receptors with βA 1-42. Furthermore, it has been shown that this interaction facilitates endocytosis of these receptors. In contrast, integrins produce their effects on the cell surface and function by associating with receptors such as NMDAR. In cultured hippocampal cells using different agonists and antagonists for NMDAR and integrins, it has been observed that the internalization of βA 1-42 peptide is regulated by integrins and influenced by NMDAR (Bi et  al., 2002). Thus, the beta amyloid 1-42 peptide is able to affect the extracellular and intracellular mechanisms involved in synaptic transmission and one of the processes involved in βA1-42 peptide internalization.

Immune cell membrane proteins associated with βA 1-42 The activation of the innate immune response through glial cells is a characteristic pathological event in AD. In particular, neuroinflammation in the brain of patients

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L.F. Hernández-Zimbrón and S. Rivas-Arancibia: Deciphering an interplay of proteins associated with amyloid β 1-42 peptide      777

with AD is associated with sites where amyloid plaques are observed, and there are increased expression levels of proinflammatory cytokines, complement components and proteases (McGeer et  al., 2006). Amyloid plaques are surrounded and infiltrated by microglial cells and astrocytes, which, to date, are known to be major components that contribute inflammatory cells in the brain. Different studies have shown that the βA peptide has the ability to activate Toll-like receptors (TLR). These receptors participate in the innate immune response and recognize structurally conserved pathogen molecules. TLRs mediate activation of microglia, subsequently resulting in neuroinflammation. This has been demonstrated using long-term treatment with non-steroid anti-inflammatory drugs that reduce the risk of AD and delay the development of the disease (Stewart et al., 1997; In’t Veld et al., 2001). This section will review the newly described associations between receptors present on immune cells of the central nervous system and beta-amyloid peptide 1-42. Toll-like receptors (TLR) are transmembrane receptors of pattern recognition that initiate signaling cascades in response to different pathogen-associated molecular patterns (PAMPs) (Kawai and Akira, 2007). To date, it is known that some TLR activation results in βA removal, although some of the mechanisms remain to be elucidated. Recently, it was determined that the type I human receptor of formyl protein coupled to G peptide (mFPR2) is highly relevant for 1-42 βA phagocytosis mediated by human macrophages. The mouse homolog, mFPR2, has recently been identified as an active participant in the removal of 1-42 βA after TLR activation in a mouse model of AD (Iribarren et al., 2005). TLR2 and TLR9 also participate in 1-42 βA removal mechanisms. These mechanisms are also dependent on the activation of mFPR2 (G-protein coupled receptor), a mechanism described in cell cultures of mouse microglia. The mechanism involved in the removal of amyloid peptide 1-42 is through activation of TLR2 and TLR9, which trigger mitogen activated protein kinases (MAPK), the subsequent expression of mFPR2 and, finally, internalization of βA 1-42. Consistent with these data, removing βA 1-42 after blocking TLR4 activation using an inhibitor of the G proteins suggests that phagocytosis induced 1-42 Aβ occurs via the TLR4 signaling pathway and requires mFPR2. This suggests that the mFPR2 acts similarly to a sensor for peptide βA in microglia activated by TLR (Du Yan et  al., 1996; Chen et  al., 2006). Analyzing these results, one might think that the inhibition or activation of this mechanism could be used as a therapy against the development or progression of AD. However, it is possible that an excessive activation of TLRs

in microglia could bring more serious consequences for the organism, such as the accumulation of cytotoxic compounds such as reactive oxygen species (ROS), cytokines, complement proteins and proteases, which lead to cell death (Li et al., 2003). The receptor for advanced glycation end products (RAGE) is another receptor involved in the dynamics of βA 1-42 removal in microglia cells and in the vascular system. The involvement of this receptor amplifies the generation of cytokines, glutamate and nitric oxide (Connor et  al., 1997; Jeynes and Provias, 2008). The binding of βA 1-42 to RAGE generates oxidative stress, which activates NFκB and enhances the expression of macrophage colony stimulating factor (M-CSF). M-CSF is produced in neurons and activates receptors in glial cells by inducing the expression of apolipoprotein E (ApoE) and macrophage scavenger receptor to ultimately stimulate proliferation and migration of glial cells. In addition, this receptor allows entry of βA 1-42 peptide into the brain parenchyma (Malherbe et al., 1999). Moreover, LRP-1 (low density lipoprotein receptor-related protein) is present in the blood brain barrier and has been shown to physically interact with the βA 1-42 peptide, facilitating its elimination in the bloodstream (Jeynes and Provias, 2008). Similarly, extensive evidence suggests that alterations in the transport of βA mediated by LRP-1 and RAGE occur in areas prone to damage in brains of patients with AD, thereby contributing to the formation of senile plaques (Coraci et  al., 2002). It is also necessary to mention that there is a secreted form of RAGE (hRAGEsec), that lacks a membrane anchoring domain, indicating that it may interact with extracellular amyloid beta peptide 1-42 and possibly mediate βA 1-42 entry into the brain parenchyma.

Other receptors In addition to the existence of interactions between the βA 1-42 peptide and the membrane receptors already mentioned, there are other βA 1-42/receptor interactions that have been studied in less detail. The following section will briefly describe some of these interactions.

CD36, CD47 and CD14 Microglia cells expressing class A scavenger receptors (SRA) and class B promote endocytosis of fibrillar βA 1-42 in suspension in neonatal microglia (Christie et al.,

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778      L.F. Hernández-Zimbrón and S. Rivas-Arancibia: Deciphering an interplay of proteins associated with amyloid β 1-42 peptide 1996). Moreover, the adhesion of microglia cells to fibrillar βA 1-42 occurs mainly in areas of the brains of AD patients where SRA is expressed in microglia compared with patients without the disease (Bamberger et  al., 2003). In later studies, it was established that CD36 is expressed on microglial cells in vitro and in brains of patients with AD and that this receptor cooperates with other receptors to stimulate the secretion of ROS by microglia and macrophages in vitro prior to interaction of βA 1-42 with CD36 (Bamberger et al., 2003, Pérez et al., 2004). Finally, the CD14 receptor also participates in the mechanisms of elimination of βA 1-42 through phagocytosis in primary cultures of microglial cells. This capture mechanism of fβA 1-42 was completely dependent on interaction with CD14 and activated microglial (Lee et al., 2001).

Peptide interactions with intracellular βA 1-42 In addition to the already mentioned associations between the βA 1-42 peptide and some extracellular or membrane proteins, this peptide has the ability also to bind to intracellular proteins, affecting or regulating their functions or pathologically activating signal transduction pathways when there is an intraneuronal accumulation of βA 1-42. One of the most studied associations is the interaction between this peptide and the Tau protein (Iqbal et al., 2005), which leads to the formation of neurofibrillary tangles found in AD and other neurodegenerative diseases known as Tauopathies. The main component is present in tangles and abnormally aggregated and insoluble hyperphosphorylated Tau protein. This pathological modification results in damaged microtubule structures and the formation of auto-aggregations of paired helical filaments. To date, enzymes have been analyzed for their ability to attach and remove phosphate residues for regulating excessive phosphorylation of Tau, thereby decreasing the negative effects of this pathological aggregation present in AD. Recent research identified that the βA 1-42 peptide binds to the microtubule binding domain of the heavy chain of microtubuleassociated protein 1B (MAP-1B) (Gevorkian et  al., 2008). This interaction may be involved in the loss of integrity of the cytoskeleton, the damage during microtubuledependent transportation and synaptic dysfunction, previously observed in Alzheimer’s disease (MungarroMenchaca et  al., 2002). In addition to binding proteins involved in intracellular transport, βA has the ability to

bind to the 20S proteasome subunit, inhibiting its activity and inducing the accumulation of ubiquitin conjugates, which directly affects cellular function (Reddy and Beal, 2008). The amyloid beta peptide has been listed as a potent mitochondrial damage agent, primarily affecting synaptic transmission. In AD, the presence of amyloid peptide inhibits mitochondrial enzymes required for the proper physiological functioning of the brain. Examples of damage caused by this malfunction correspond to an improper electron transport in the respiratory chain, decreased ATP production, high consumption of oxygen and changes in membrane potential, as well as the formation of the superoxide radical and the conversion to hydrogen peroxide that causes oxidative stress, release of cytochrome C and apoptosis (Hirai et al., 2001; Hernández-Zimbrón et al., 2012). A specific example of the damage caused by βA 1-42 peptide interacting with mitochondrial proteins is a dysfunction of the alcohol dehydrogenase (amyloid betapeptide binding alcohol dehydrogenase, ABAD). This interaction occurs in the mitochondria of AD patients and in transgenic mice. This interaction distorts the active site, affecting the binding of nicotinamide adenine dinucleotide (NAD), which generates high neuronal oxidative stress and transiently affects memory (Lustbader et  al., 2004). Other studies have shown that βA interacts with the intracellular protein known as a binding protein to endoplasmic reticulum beta amyloid peptide (ERAB) that operates as a L-3-hydroxyacyl-CoA dehydrogenase type II (He et  al., 1998; Yan and Stern, 2005). This interaction may promote mitochondrial dysfunction and thus cell death, suggesting that inhibition of the interaction βA-ERAB can also function as a new treatment strategy for AD (Casley et al., 2002).

Importance of the presence of βA peptide in mitochondria and mitochondrial dysfunction in AD Mitochondria are subcellular organelles essential to the generation of energy (ATP) through the electron transport chain (ETC) to maintain cellular function. These organelles can monitor cellular physiology to respond to different stimuli for the survival of the cell and may initiate programmed cell death. The amyloid beta peptide has been listed as a potent mitochondrial damage agent, affecting synaptic transmission. Examples of damage caused by the

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L.F. Hernández-Zimbrón and S. Rivas-Arancibia: Deciphering an interplay of proteins associated with amyloid β 1-42 peptide      779

malfunction correspond to incorrect electron transport in the respiratory chain, decreased ATP production, high consumption of oxygen, and changes in mitochondrial membrane potential. Moreover, the formation of the superoxide radical and conversion to hydrogen peroxide cause oxidative stress, release of cytochrome C and apoptosis. It has been proposed that these apoptotic mechanisms are activated when there is a power failure due to processes that inhibit ETC, toxic damage involved in the proper functioning of the ETC, or components that increase cellular vulnerability (Kwong et al., 2007; Pahnke et al., 2013). Several years ago, Swerdlow, Burns and Khan (Swerdlow et  al., 2010) proposed the mitochondrial cascade hypothesis to explain late developing and sporadic AD. This hypothesis postulates that in AD of sporadic origin, mitochondrial dysfunction is the first event that causes the accumulation of the βA peptide, synaptic degeneration and the formation of neurofibrillary tangles. Currently, there many studies showing that mitochondrial dysfunction is a common event in AD. Glucose metabolism is reduced in the brain of patients with mild cognitive impairment along with alterations in the activity of mitochondrial enzymes (Liang et al., 2008). These metabolic alterations in early stages of the disease and in patients diagnosed with AD correspond to ETC damage, particularly in the activity of the cytochrome C oxidase enzyme (HernándezZimbrón et al., 2012; Bobba et al., 2013). Experiments in transgenic mice have demonstrated the presence of this peptide within cellular organelles, which correlate with the magnitude of mitochondrial dysfunction caused by the inhibition of the ETC and with the degree of cognitive damage observed in this model of AD (Ghosh et al., 2013). Moreover, it has been shown that βA 1-42 can induce the opening of mitochondrial permeable pores in mouse neurons and that the presence of this peptide in mitochondria inhibits the activity of the protein cytochrome C oxidase (CcOX) in neurons of transgenic mice. Some authors have suggested that the mitochondrial dysfunction and energy deficits observed in AD may be caused by the inhibition of CcOX caused by βA peptide binding to one of its subunits. Previously, we identified two mitochondrial enzymes that have the ability to bind to βA 1-42. The first corresponds to the human protein complex I (ND3) (Munguia et al., 2006), and the second is subunit I of cytochrome c oxidase (Hernández-Zimbrón et al., 2012). This association could explain the inhibition of mitochondrial complex I activity in astrocytes and neurons in the presence of βA, as recently described.

Other interactions The 34 allele of the apolipoprotein E (APOE) is the major risk factor in AD, and several researchers have suggested that each of the apoE isoforms have different effects on the addition and deletion of βA. In vitro studies have shown that the interaction between apoE isoforms and βA influences the aggregation process of βA in vitro. apoE4 free form lipid forms stable complexes with βA rather than apoE3 (Sanan et al., 1994). Subsequent studies mention that apoE2 and apoE3 associated with lipids form more complexes compared with apoE4. Furthermore, it has been demonstrated that formation of βA/apoE isoform complexes happens in the order of apoE2 > apoE3 > > apoE4. The latter study proposed that apoE2 and apoE3 can participate in the removal of βA, unlike apoE4. Furthermore, it has been shown that the binding site of βA for apoE corresponds to amino acid residues 12 to 28 (Jiang et al., 2008). Moreover, apoE4 facilitates binding and internalization of soluble βA in several neuronal cell lines. Finally, apoE4/βA complexes present in the periphery of the blood brain barrier are sequestered into the capillaries of the brain, which occurs to a greater extent for apoE4 than for apoE2 and apoE3, suggesting that apoE4 mediates the transport across the blood brain barrier. Additionally, apoE4 plays an important role in βA accumulation in the brain (Cramer et al., 2012). IDE is a metalloproteinase that contains zinc (Zn), catalyzes the degradation of amylin, insulin and glucagon, and participates in the degradation of monomeric forms of βA 1-40 and βA 1-42 (Duckworth et  al., 1998; NeantFery et al., 2008). Existing evidence in rodent models and human genetic analysis have shown that the activity of IDE is critical in determining the levels of amyloid peptides. Therefore, many researchers have focused on trying to develop enzyme activators for the treatment of AD (Kim et al., 2007). In a more recent study, it was demonstrated that the βA 1-42 peptide is more flexible than βA 1-40 due to the presence of two hydrophobic residue residents in βA 1-42 (Ile41 and Ala42), which change the way the βA 1-42 interacts with IDE. These structural phenomena correspond to the formation of intermolecular hydrogen bonds (17–22) with IDE (Cabrol et al., 2009). However, at the extreme C-terminus, βA 1-42 forms more hydrogen bonds with IDE compared to βA 1-40. Furthermore, it has been shown that βA 1-42 generates some intramolecular interactions within IDE and adopts a β sheet structure in the environment of IDE, facilitating its degradation (Bora and Prabhakar, 2010). Such studies help us to understand atomic-level details of the conformations and interactions of βA 1-42 and βA 1-40 in the catalytic site of IDE and aid

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780      L.F. Hernández-Zimbrón and S. Rivas-Arancibia: Deciphering an interplay of proteins associated with amyloid β 1-42 peptide our understanding of the mechanisms of binding and degradation of these peptides by this enzyme. Myelin basic protein (MBP) is an important protein in the process of myelination of nerves in the central nervous system. In previous research, it has been shown that MBP binds to βA 1-42 and βA 1-40. This interaction inhibits the fibrillar ensemble of these peptides in vitro, preventing the formation of the β sheet (Hoos et al., 2007; Eisenberg and Jucker, 2012). Furthermore, active microglia secrete MBP (Jakovcevski et al., 2009). These discoveries might suggest that endogenous MBP could regulate the fibril ensemble and βA 1-42 accumulation in AD. Further studies are needed to demonstrate the relevance of this interaction and to try to determine some therapy against the development and progression of AD.

G protein-coupled receptors and cholinergic malfunction in AD Recently, it has been reported that several species of βA peptide lead to deregulation of cholinergic function, which is characterized by a decrease in the release of acetylcholine as well as by changes in the coupling of muscarinic acetylcholine receptors (mAChRs) to GTP binding proteins (G proteins). Although the mechanism of medium toxicity by βA 1-42 is not well understood, the evidence demonstrates that βA sequesters the alpha subunit (q11) family of G proteins, resulting in the disruption of the coupling between muscarinic acetylcholine receptors and G proteins and eventually leading to neurotoxicity in AD (Thathiah and De Strooper, 2009). Therefore, it is necessary to continue with studies proving the physical interaction of βA 1-42 with other G protein subunits and the effects of the interaction. More recently, we identified an interaction between beta amyloid 1-42 peptide and the alpha subunit of these G protein-coupled receptors (unpublished data). As we have reviewed above, there are important findings in studies of protein interactions in AD. Despite these advances, we have not fully understood the mechanisms involved in the pathology of the disease. Therefore, it is necessary to continue investigating the interactions in greater depth to develop possible therapies for the prevention and attenuation of the development or progression of AD.

Conclusions AD is a progressive neurological disorder that has been associated with memory loss and aberrant behavior in

diagnosed patients. The disease is caused by loss of synaptic integrity and neuronal loss in brain areas associated with learning and memory. A primary event in this disease is the accumulation and pathological aggregation of β-amyloid peptide 1-42, but despite the recent research, the mechanisms of the neurotoxicity of this peptide have not been shown in their entirety. However, there are salient findings that indicate that the gain or loss of the function of some proteins reported in AD is due to the interaction of the βA peptide with membrane or intracellular proteins. Due to the nature of the peptide, βA is capable of binding to a variety of biomolecules, including structural proteins in cell membranes, extracellular receptors and intracellular proteins. Interactions between βA 1-42 peptide and proteins have been widely reported in trying to understand the mechanisms of neurotoxicity, such as (1) the self-neurotoxicity that generates the βA, (2) the damage on intracellular structures as well as transport into the cell, (3) the inhibition of cell signaling cascades, (4) cellular protection mechanisms due to the removal and degradation of βA 1-42 by local immune cells, (5) the generation of reactive oxygen species that generate toxic oxidative stress in the cell and, (6) finally, cell death. Acknowledgments: Funding was provided by DGAPAUNAM (IN221114); LFHZ is a recipient of a postdoctoral scholarship from Programa de Becas Posdoctorales, DGAPA-UNAM, México. The authors thank Varsha Velumani and Subramaniam Velumani for comments and English translation and Gevorkian G for valuable comments.

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Luis Fernando Hernández-ZimbrÓn is currently a postdoctoral fellow in the Oxidative Stress and Neuronal Plasticity Laboratory of the Faculty of Medicine at National Autonomous University of Mexico (UNAM) at México City, Mexico. Hernández-Zimbrón earned a Bachelor’s degree in Biology from the Faculty of Sciences at UNAM and received with honors his Doctoral degree in Biomedical Science from the Biomedical Sciences Institute at the National Autonomous University of Mexico. He is working in the field of oxidative stress in Alzheimer’s disease (AD).

Selva Rivas-Arancibia received her MD from the Faculty of Medicine at UNAM and received her Masters and PhD degrees in Biomedical ­Sciences at the same University. Currently she is Professor of Human Phisiology at the Faculty of Medicine. Dr. Rivas research interest includes ozone pollution, oxidative stress and neurodegenerative process. She is also interested in understanding the changes in the immune system caused by oxidative stress, as an inflammatory response, and the molecular mechanisms in neurodegenerative disease.

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