Alzheimer's disease genes and autophagy

Author’s Accepted Manuscript Alzheimer's disease genes and autophagy Seung-Yong Yoon, Dong-Hou Kim

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To appear in: Brain Research Received date: 18 October 2015 Revised date: 9 March 2016 Accepted date: 13 March 2016 Cite this article as: Seung-Yong Yoon and Dong-Hou Kim, Alzheimer's disease genes and autophagy, Brain Research, http://dx.doi.org/10.1016/j.brainres.2016.03.018 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 galley proof before it is published in its final citable 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.

Alzheimer’s disease genes and autophagy Seung-Yong Yoona,b,c,d,* and Dong-Hou Kima,b,c,d,* a

Alzheimer’s Disease Experts Lab (ADEL), Asan Institute of Life Sciences, Asan Medical Center,

University of Ulsan College of Medicine, Seoul, Korea b

Department of Brain Science, University of Ulsan College of Medicine, Seoul, Korea

c

Bio-Medical Institute of Technology (BMIT), University of Ulsan College of Medicine, Seoul, Korea

d

Cell Dysfunction Research Center (CDRC), University of Ulsan College of Medicine, Seoul, Korea

*Co-corresponding authors: Seung-Yong Yoon and Dong-Hou Kim, Alzheimer Disease Experts Lab (ADEL), Department of Brain Science, University of Ulsan College of Medicine, 88, Olympic-ro 43gil, Songpa-Gu, Seoul 138-736, Korea. Tel: 82-2-3010-4241; Fax: 82-2-3010-8038; E-mail: [email protected], [email protected] Abstract Autophagy is a process to degrade and recycle cellular constituents via the lysosome for regulating cellular homeostasis. Its dysfunction is now considered to be involved in many diseases, including neurodegenerative diseases. Many features reflecting autophagy impairment, such as autophagosome accumulation and lysosomal dysfunction, have been also revealed to be involved in Alzheimer’s disease (AD). Recent genetic studies such as genome-wide association studies in AD have identified a number of novel genes associated with AD. Some of the identified genes have demonstrated dysfunction in autophagic processes in AD, while others remain under investigation. Since autophagy is strongly regarded to be one of the major pathogenic mechanisms of AD, it is necessary to review how the AD-associated genes are related to autophagy. We anticipate our current review to be a starting point for future studies regarding AD-associated genes and autophagy. Abbreviations AD, Alzheimer’s disease; APP, amyloid precursor protein; A, -amyloid; PS1/2, presenilin 1/2, APOE, apolipoprotein E; ADAM10, a disintegrin and metallopeptidase domain 10; TREM2, triggering receptor expressed on myeloid cells 2; BECN1, beclin-1; SNP, single nucleotide 1

polymorphism; PICALM, phosphatidylinositol-binding clathrin assembly protein; CR1, complement component 3b/4b receptor 1; BIN1, bridging integrator 1; MS4A6A/E, membrane-spanning 4 domains subfamily A/E member 6A; ABCA7, ATP-binding cassette subfamily A member 7; CD2AP, CD2-associated protein; EPHA1, ephrin receptor A1; EPHB2, ephrin receptor B2; HLA-DRB5/1, major histocompatibility complex class II DR5/1; SORL1, sortilin-related receptor L A repeats containing; PTK2B, protein tyrosine kinase 2; SLC24A4, solute carrier family 24 member 4; ZCWPW1, zinc finger CW-type with PWWP domain 1; CELF1, CUGBP Elav-like family member 1; FERMT2, fermitin family member 2; CASS4, Cas scaffolding protein family member 4; INPP5D, inositol polyphosphate-5 phosphatase 145 kDa; MEF2C, myocyte enhancer factor 2C; NME8, NME/NM23 family member 8; PLD3, phospholipase D3 Keywords TAU; APP; amyloid; presenilin; APOE; TREM2 1. Introduction 1.1. Alzheimer’s disease Alzheimer’s disease (AD), the most common neurodegenerative disease, is characterized by progressive impairment of cognitive function and memory formation. Pathological signalling in AD is largely mediated by two major characteristic components, neurofibrillary tangles (NFTs) and senile plaques (Gomez-Isla et al., 1997). Extracellular plaques are primarily composed of amyloid- (A) peptides, which are derived from amyloid precursor protein (APP) via proteolytic processing. NFTs are formed by intraneuronal accumulation of paired helical filaments composed of abnormally hyperphosphorylated TAU protein (Grundke-Iqbal et al., 1986).

1.2. Autophagy Macroautophagy (hereafter, autophagy) is a catabolic process that sequesters cytoplasm, including aberrant organelles and macromolecules, into double-membrane vesicles and delivers this material to lysosomes for degradation and the eventual recycling of the resulting macromolecules (Castellano et 2

al., 2011b). Under the control of various signalling and protein assemblies from certain stimuli, such as starvation, damaged organelles, or protein aggregates, the first step of autophagy begins with the formation of an isolation membrane (phagophore). The isolation membrane elongates around the molecules and organelles to be degraded, closing its inner and outer bilayers to form a doublemembrane autophagosome. The autophagosome then fuses with a lysosome that degrades the autophagosome contents (Hale et al., 2013; Klionsky, 2012). Impairment or misregulation in these steps of autophagy is associated with many neurodegenerative diseases, including AD (Nixon, 2013).

1.3. Autophagy in AD Marked accumulation of autophagosomes and late autophagic vacuoles is observed in dystrophic neurites of AD brains, animal AD model brains, and AD cellular models, suggesting impaired fusion with or degradation by lysosomes (Yoon et al., 2008; Yu et al., 2004; Yu et al., 2005). Nixon (Nixon, 2013) recently reviewed the relationship between impaired lysosomal function and autophagy in neurodegenerative diseases, including AD. In our present review, we discuss the association of AD genes with autophagy in an attempt to understand how autophagy is involved in the pathogenesis of AD and how therapeutic approaches for AD could exploit autophagic pathways.

2. Autophagy-related features and roles of AD-associated genes 2.1. Genes associated with AD The classical genes associated with early-onset familial AD are APP, presenilin 1 (PS1), and presenilin 2 (PS2). Apolipoprotein E (APOE) is the strongest risk factor for late-onset AD (Guerreiro et al., 2013b; Karch and Goate, 2015). Recent genetic studies have identified numerous novel gene loci affecting late-onset AD (Table 1).

2.2. APP and A APP is a type I membrane protein that is sequentially cleaved by -secretase and -secretase to 3

generate A peptide, a major constituent of the senile plaques of AD. More than 30 mutations in APP are associated with early-onset familial AD (Guerreiro et al., 2012; http://www.molgen.vibua.be/ADMutations). Autophagy has been suggested to lead to A generation since the first report proposing the role of autophagy in AD because early studies demonstrated that autophagosomes accumulate within AD neurites, and APP, CTFs of APP, A, and BACE were found within these autophagosomes (Mizushima, 2005; Nixon, 2007; Yu et al., 2004; Yu et al., 2005). However, further understanding of autophagy itself and its relationship with AD led to the identification of APP, A, APP-CTFs, and BACE as autophagy substrates (Cho et al., 2014; Jaeger et al., 2010; Liu et al., 2013; Lunemann et al., 2007; Pickford et al., 2008; Tian et al., 2013; Zhou et al., 2011). In support of this view, various compounds, such as rapamycin, trehalose, carbamazepine, latrepirdine, arctigenin, temsirolimus, and curcumin, have been suggested to help protect against AD by degrading A and other related pathogenic proteins via activation of autophagy (Jiang et al., 2014a; Li et al., 2013; Perucho et al., 2012; Steele and Gandy, 2013; Tian et al., 2011; Wang et al., 2014; Zhu et al., 2013). A direct role of APP or A in autophagy has not been determined yet, but AD-related mutations in APP may contribute to AD pathogenesis by producing impaired autophagy functions. Such mutations are known to generate more A and aggregation-prone A, which results in an overloaded autophagic pathway due to accumulated substrates. Aβ directly interacts with membranes via its hydrophobic carboxyl terminus (Masters and Selkoe, 2012), which is suggested to interfere with normal biogenesis and trafficking of intracellular organelles (Kakio et al., 2004; Murphy, 2007; Sasahara et al., 2013). This feature of A may also affect the biogenesis or trafficking of autophagosomes and their fusion with lysosomes, and this possibility needs to be addressed in the future. A accumulation in lysosomes results in lysosomal membrane destabilization and leakage (Ji et al., 2002; Yang et al., 1998), which may also impair autophagy and lysosomal degradation (Nixon, 2013).

4

2.3. Presenilin Presenilins 1 and 2 are homologous integral membrane proteins containing nine transmembrane domains (Guerreiro et al., 2012). Presenilin 1/2 forms the -secretase complex with nicastrin, anterior pharynx-defective 1 (APH1A/B), and presenilin enhancer 2 (PEN2) to cleave APP into A (Wakabayashi and De Strooper, 2008). Approximately 200 mutations in the presenilins have been reported to lead to altered A42/A40 ratios and to account for early-onset familial AD (Guerreiro et al., 2012; http://www.molgen.vib-ua.be/ADMutations). Besides its function of as a -secretase for A generation, presenilin is also necessary for efficient lysosomal proteolysis, and hence autophagy, by regulating vATPase-mediated lysosome acidification, and its mutations disrupt these lysosomal functions and autophagy (Lee et al., 2010; Neely et al., 2011; Wilson et al., 2004).

2.4. ADAM10 ADAM10 (a disintegrin and metallopeptidase domain 10) is a major -secretase involved in APP cleavage that precludes the formation of A (Jorissen et al., 2010; Kuhn et al., 2010; Postina et al., 2004). Rare coding variants in ADAM10 are associated with late-onset AD families (Kim et al., 2009b). There are no reports associating ADAM10 with autophagy and AD, but it was recently reported that the ADAM10 levels can be regulated by autophagy in endothelial cells and in turn regulates the susceptibility of mice to endothelial ADAM10-related disease status (Maurer et al., 2015). Hence, there’s possibility that ADAM10 in neurons and glia could be also regulated by autophagy. The regulation of neuronal and glial ADAM10 by autophagy and the effects of the ADassociated variants of ADAM10 on autophagy need to be addressed in the future.

2.5. TAU TAU attaches to and stabilizes microtubules. An indispensable pathological hallmark for AD diagnosis is NFTs, of which the main constituent is TAU protein. Autophagy requires the movement 5

of autophagosomes and lysosomes along microtubules (Kochl et al., 2006; Mackeh et al., 2013). Hence, TAU deletion destabilizes microtubules and impairs autophagy, and thereby exacerbates the phenotypes of Niemann-Pick type C mice and A accumulation (Lonskaya et al., 2014; Pacheco et al., 2009a; Pacheco et al., 2009b). TAU, especially TAU aggregates, is a substrate for autophagy, suggesting that impaired autophagy in AD may contribute to the formation of TAU aggregates, resulting in increased NFTs (Wang et al., 2009; Wang et al., 2010a; Wang et al., 2010b). A form of TAU-cleaved fragments was suggested to bind abnormally tightly to lysosomal membrane-associated protein 2A (LAMP2A), which is a core component of chaperone-mediated autophagy, another form of autophagy (Wang et al., 2009; Wang et al., 2010b). Various compounds, such as rapamycin, trehalose, and temsirolimus, have been suggested to protect against AD by activating autophagy and degrading pathological TAU (Frederick et al., 2015; Jiang et al., 2014b; Kruger et al., 2012; Ozcelik et al., 2013; Rodriguez-Navarro et al., 2010; Schaeffer et al., 2012). Nuclear domain 10 protein 52 (NDP52, CALCOCO2) is one of the autophagic receptors that selectively degrades substrates by autophagy. Phosphorylated TAU is cleared by autophagy via NDP52 (Jo et al., 2014; Kim et al., 2014).

2.6. APOE APOE is a class of apolipoprotein primarily produced by the liver and macrophages in peripheral tissues. In the central nervous system, APOE is mainly produced by astrocytes and transports cholesterol to neurons via APOE receptors (DeMattos et al., 2004; Lesuisse et al., 2001). APOE exists as three isoforms that differ according to two amino acid residues (112 and 158): APOEε2, APOEε3, and APOEε4. APOEε3 is the most common APOE isoform, and APOEε4 increases the risk of familial and sporadic AD 3-fold for heterozygous carriers and 8- to 10-fold for homozygous carriers (Guerreiro et al., 2012). APOEε2 decreases the risk for late-onset AD and delays the age of onset (Guerreiro et al., 2012). APOE binds to A, influencing the clearance of A (Castellano et al., 2011a; Kim et al., 2009a), and APOE4 accelerates A fibril formation and increases intraparenchymal A deposits (Fagan et al., 2002; Sanan et al., 1994; Strittmatter et al., 1993). Hence, APOE4-induced 6

increases in the amount of A and its aggregation may contribute to impaired autophagy in AD. Moreover, APOE4 itself potentiates A-induced lysosomal membrane destabilization and its leakage (Ji et al., 2002; Ji et al., 2006), which may impair autophagy and lysosomal degradation (Nixon, 2013).

2.7. TREM2 TREM2 is an innate immune receptor expressed on the cell membrane of a subset of myeloid cells, such as microglia, dendritic cells, osteoclasts, and macrophages. TREM2 may function in myeloid cells, most probably osteoclasts and microglial cells, both of which are involved in bone remodeling and brain function (Cella et al., 2003). Its latter function is regulated by glycosylation (Kleinberger et al., 2014; Park et al., 2015). A recent genome-wide association study (GWAS) of TREM2 suggested a possible role in the progression of late-onset AD (Jiang et al., 2013). The odds ratios of TREM2 variants are similar to those of the APOE4 alleles. TREM2 was also found to be upregulated in microglia in AD transgenic mouse models (Frank et al., 2008; Melchior et al., 2010). Recently, several TREM2 mutations have also been reported to cause a fronto-temporal dementia-like syndrome without bone pathology (Guerreiro et al., 2013a; Guerreiro et al., 2013c). TREM2 expressed on microglia plays a critical role in clearing neural debris in the lesioned central nervous system (Lucin et al., 2013). The AD-associated R47H variant of TREM2 reduces A phagocytosis by microglia (Kleinberger et al., 2014). APOE is a ligand for TREM2, and APOE cannot bind to the R47H variant (Atagi et al., 2015; Bailey et al., 2015). Recycling of TREM2 in microglia is regulated by beclin-1 (BECN1), a protein involved in autophagy. BECN1 levels are reduced in the microglia of AD brains, which is associated with impaired recycling of TREM2 and impaired phagocytosis (Lucin et al., 2013). Therefore, additional relationships between TREM2 and autophagy are expected to be revealed.

2.8. PICALM PICALM is predominantly expressed in neurons (Xiao et al., 2012) and is implicated in clathrinmediated endocytosis and synaptic vesicle trafficking (Baig et al., 2010; Harel et al., 2008; Wendland 7

et al., 1998; Zhang et al., 1998). GWASs identified PICALM as a risk-modulating gene in AD (Harold et al., 2009; Lambert et al., 2009). PICALM alters APP trafficking and modulates A plaque deposition and A-induced toxicity (Treusch et al., 2011; Xiao et al., 2012). PICALM interacts with LC3 and targets APP-CTF for degradation via autophagy (Tian et al., 2013). PICALM influences autophagy by regulating the endocytosis of SNAREs and modulates TAU accumulation (Moreau et al., 2014).

2.9. Clusterin Clusterin (apolipoprotein J) is a stress-activated chaperone protein (Jones and Jomary, 2002). Various single nucleotide polymorphisms (SNPs) in clusterin are related to AD (Harold et al., 2009; Hollingworth et al., 2011; Lambert et al., 2009; Lambert et al., 2013; Naj et al., 2011). Numerous studies have investigated the relationship between AD and clusterin and the role this chaperone plays in the disease. Clusterin is found in A plaques (Calero et al., 2000; Matsubara et al., 1995), interacts with A, and alters the solubility and aggregation of A (Matsubara et al., 1995; Matsubara et al., 1996; Oda et al., 1995). The expression of clusterin mRNA is elevated in AD brains (Allen et al., 2012; Karch et al., 2012). Clusterin was recently reported to facilitate LC3 lipidation and to induce autophagosome formation under stress conditions in cancer (Zhang et al., 2014). Therefore, the relationship of clusterin with autophagy and their effect on neurodegeneration needs to be addressed in the future.

2.10. CD2AP CD2AP is a scaffolding protein that regulates the actin cytoskeleton and membrane dynamics through its SH3 domains (Dustin et al., 1998). Various SNPs in CD2AP are related to AD (Hollingworth et al., 2011; Lambert et al., 2013; Naj et al., 2011; Shulman et al., 2013). Knockdown of CD2AP in a Drosophila AD model aggravates TAU neurotoxicity (Shulman et al., 2011). With respect to autophagy, CD2AP regulates vesicular trafficking to the lysosome, and CD2AP deficiency impairs 8

lysosomal function (Cormont et al., 2003), implicating CD2AP in autophagy.

2.11. Ephrin A1 Ephrin A1 (EPHA1) is a member of the ephrin family of receptor protein tyrosine kinases involved in developmental processes, particularly those of the nervous system (Flanagan and Vanderhaeghen, 1998). Several SNPs near EPHA1 are associated with AD (Hollingworth et al., 2011; Lambert et al., 2013; Naj et al., 2011). Ephrin B2 (EPHB2) induces autophagy in human breast cancer cells (Chukkapalli et al., 2014). EPHA1 and EPHB2 are involved in the induction of autophagy in colon cancer cells by sesamin (Tanabe et al., 2011). Therefore, EPHA1 is also expected to play a role in autophagy in the nervous system and in AD, so future studies will be necessary.

2.12. PLD3 Phospholipase D3 (PLD3) is a poorly characterized member of the PLD family that may hydrolyze phosphatidylcholine to phosphatidic acid (McDermott et al., 2004; Munck et al., 2005). PLD3 is a type 2 transmembrane protein with high expression levels in the frontal and temporal cortices and hippocampus, especially in neurons (Cruchaga et al., 2014; Hawrylycz et al., 2012; Lein et al., 2007). Compared to PLD1, PLD2, and other AD risk genes (Karch and Goate, 2015), little is known about the role of PLD3 in AD. PLD3 is moderately reduced and accumulated on neuritic plaques in AD brains (Satoh et al., 2014), suggesting that it plays a key role in the pathological processes of AD. A genetic association between AD risk and several rare coding variants in the PLD3 gene have been reported (Cruchaga et al., 2014). That study identified three PLD3 variants—Val232Met, Ala442Ala, and Met6Arg—as strong risk factors for AD. However, three groups all reported in 2015 that they failed to find an association between these PLD3 variants and AD risk (Heilmann et al., 2015; Hooli et al., 2015; Lambert et al., 2015). Another group found a nominal association between the PLD3 variant Val232Met and AD risk (van der Lee et al., 2015). Hence, there are furious debates about whether PLD3 is indeed an AD risk factor, and further genetic studies and biological studies are 9

necessary to reach a firm conclusion. Although there are no reports on PLD3 and autophagy, PLD1 and PLD2 regulate autophagy (Bae et al., 2014; Dall'Armi et al., 2010; Hwang et al., 2014; Jang et al., 2014); therefore, PLD3 is also expected to play roles in autophagy, an aspect that needs to be addressed in the future.

2.13. SORL1 SORL1 (alternatively, SORLA, LR11) is a neuronal APOE receptor predominantly expressed in the central nervous system (Scherzer et al., 2004). SORL1 regulates vesicle trafficking from the cell surface to the Golgi apparatus and the endoplasmic reticulum. SORL1 expression is significantly reduced in AD brains (Scherzer et al., 2004). Recent genetic studies have revealed an association between SORL1 and AD (Allen et al., 2012; Baig et al., 2010; Lambert et al., 2013). Not much is yet known about the roles of SORL1 in autophagy. However, it was recently reported that SORL1 binds to A via its N-terminal VPS10P domain and delivers A to lysosomes for its degradation, and that SORL1 mutations impair its A-binding and sorting (Caglayan et al., 2014).

2.14. BIN1 BIN1 (alternatively, amphiphysin II, box-dependent myc-interacting protein 1) is a novel human gene product that interacts with the myc oncoprotein with features of a tumor suppressor (Negorev et al., 1996). BIN1 has several alternately spliced forms that are expressed in a cell type-specific manner, including brain-specific forms (Wechsler-Reya et al., 1997). The BIN1 knock-out in mouse brains manifested major learning deficits and seizures with defects in synaptic vesicle recycling (Di Paolo et al., 2002). BIN1 was identified to be a risk factor for late-onset AD from GWASs (Harold et al., 2009; Lambert et al., 2013; Naj et al., 2011). BIN1 is implicated in TAU-induced toxicity (Chapuis et al., 2013). This protein is also involved in membrane curvature induction, endocytosis, and intracellular endosome trafficking (Di Paolo et al., 2002; McMahon et al., 1997; Ramjaun and McPherson, 1998; Tsutsui et al., 1997; Wigge and McMahon, 1998), which may affect the trafficking and processing of 10

APP and the biogenesis of amphisomes and autophagosomes. Although a direct role of BIN1 in the autophagy pathway remains to be reported, it is notable that structurally related BAR domaincontaining proteins such as SH3 domain-containing protein 2 (SH3P2) translocate to the preautophagosomal membrane after autophagy induction and play a role in autophagosome formation (Jungbluth and Gautel, 2014; Zhuang et al., 2013).

2.15. Other AD-related genes In addition to the AD-related genes described above, many other genes have been associated with AD. There are almost no reports on the potential relationship between these genes and autophagy. Accumulating knowledge may reveal relationships among these genes, autophagy, and AD pathogenesis in the future.

3. Conclusions APP, A, ADAM10, and TAU are autophagy substrates. Presenilin, PICALM, clusterin, CD2AP, and EPHA1 regulate autophagy through various mechanisms as summarized in Table 1. Recent updates in AD genetic studies have markedly increased the number of genes found to be related to AD, and their pathogenic roles in AD should be elucidated in the coming years. These genes may also have a relationship with autophagy, which may itself play a role in AD pathogenesis.

Acknowledgments This work was supported by Medical Research Center Program through the National Research Foundation of Korea(NRF) funded by the Ministry of Science, ICT & Future Planning(20080062286).

11

12

Figure Legend Figure 1. The potential roles of AD-associated genes in autophagy -amyloid (A), amyloid precursor protein (APP), its C-terminal fragments (APP-CTF), -secretase (ADAM10) and phosphorylated TAU (p-TAU) are substrates for autophagic degradation. Ephrin receptor A1 (EPHA1) is involved in autophagy induction. SORL1 delivers A for lysosomal degradation and p-TAU is degraded by autophagy via NDP52. PICALM regulates the degradation of APP-CTF and TAU by autophagy. Clusterin facilitates LC3 lipidation and induces autophagosome formation. TAU stabilizes microtubules and helps autophagosome delivery. A and APOE4 induce lysosomal membrane destabilization and permeabilization.

Table 1. The potential roles of AD-associated genes in autophagy Gene

Gene name

Generally known/suggested

13

Potential role and relation with

symbol

functions

autophagy

APP,

Amyloid precursor

APP is cleaved by  and -

APP and A are autophagy substrates

A

protein,

secretase, generating A.

(Cho et al., 2014; Jaeger et al., 2010; Liu et al., 2013; Lunemann et al., 2007; Pickford et al.,

-amyloid

2008; Tian et al., 2013; Zhou et al., 2011).

impairs

autophagy

and

A

lysosomal

degradation (Ji et al., 2002; Nixon, 2013; Yang et al., 1998).

PSEN1/2

Presenilin 1/2

Presenilin

is

the

catalytic

component of -secretase.

Presenilin

regulates

lysosomal

acidification and autophagy (Lee et al., 2010; Neely et al., 2011; Wilson et al., 2004).

ADAM10

TAU

-

A disintegrin and

ADAM10

metallopeptidase

secretase and may preclude A

domain 10

generation.

TAU

TAU stabilizes microtubules, TAU stabilizes microtubules and helps

functions

as

ADAM10 levels are regulated by autophagy (Maurer et al., 2015).

and hyperphosphorylated TAU

autophagy (Lonskaya et al., 2014; Pacheco et

forms neurofibrillary tangles.

al.,

2009a;

Pacheco

et

al.,

2009b).

Phosphorylated TAU is degraded by autophagy via NDP52 (Jo et al., 2014; Kim et al., 2014).

APOE

Apolipoprotein E

APOE functions as a lipoprotein

APOE4

and the E4 allele raises AD risk.

lysosomal membrane destabilization

potentiates

A-mediated

and permeabilization (Ji et al., 2002; Ji et al., 2006).

TREM2

Triggering receptor

TREM2 regulates phagocytosis

TREM2 recycling is regulated by

expressed

and immune responses.

BECN1 (Lucin et al., 2013).

PICALM interacts with clathrin

PICALM regulates the degradation of

on

myeloid cells 2 PICALM

Phosphatidylinosito

14

l-l-binding clathrin

heavy chain.

APP-CTF and TAU by autophagy

assembly protein CLU

(Moreau et al., 2014; Tian et al., 2013).

Clusterin, APOJ

Clusterin acts as a chaperone

Clusterin facilitates LC3 lipidation and

and is implicated in apoptosis.

induces

autophagosome

formation

(Zhang et al., 2014).

CD2AP

CD2-associated

CD2AP is a scaffolding protein

CD2AP regulates vesicular trafficking

protein

that

to the lysosome (Cormont et al., 2003).

regulats

the

actin

cytoskeleton. EPHA1

PLD3

EPH receptor A1

EPHA1

Phospholipase D3

is

implicated

in

Ephrin A1 is involved in the induction

mediating brain development.

of autophagy (Tanabe et al., 2011).

PLD3 putatively acts as a

Not known. PLD1 induces autophagy

phospholipase.

(Bae et al., 2014; Dall'Armi et al., 2010; Hwang et al., 2014; Jang et al., 2014).

SORL1

Sortilin-related

SORL1 is a neuronal APOE

SORL1 delivers A for lysosomal

receptor,

L(DLR

receptor.

degradation (Caglayan et al., 2014).

class)

repeats

A

containing BIN1

CR1

MS4A6A

Bridging integrator

BIN1 may be involved

in

Not known

1

synaptic vesicle endocytosis.

Complement

CR1 mediates cellular binding

Not known

component (3b/4b)

of

receptor

activate complement.

Membrane-

MS4A6A may be involved in

spanning

MS4A4E

4

immune

signal

complexes

transduction

domains, subfamily

component of a

A, member 6A

receptor complex.

Membrane-

MS4A4E

spanning

4

as

that

a

multimeric

may have similar

function with MS4A6A.

15

Not known

Not known

domains, subfamily A, member 4E CD33

CD33 molecule

CD33 is expressed on myeloid

Not known

cells and binds sialic acid. ABCA7

ATP-binding

ABCA7

is

expressed

cassette, subfamily

predominantly

A (ABC1), member

lymphatic

7

implicated in lipid homeostasis.

HLA-

Major

HLA-DRB5/1

DRB5 and

histocompatibility

MHC.

DRB1

complex, class II,

in

myelo-

tissues

is

Not known

and

a

is

class-II

Not known

PTK2B is involved in calcium-

Not known

DR beta 5 and DR beta 1 PTK2B

Protein

tyrosine

kinase 2 beta

induced

regulation

of

ion

channels. SLC24A4

Solute

carrier

family

24

SLC24A4 is involved in brain

Not known

and neural development.

(sodium/potassium/ calcium exchanger), member 4 ZCWPW1

Zinc

finger,

CW

Not known

Not known

type with a PWWP domain CELF1

CASS4

CUGBP, ELAV-like

CELF1

pre-mRNA

Not known

family member 1

splicing.

Cas

scaffolding

CASS4 may be involved in

Not known

family

cytoskeleton reorganization and

protein

regulates

16

member 4

motility by FAK and SRC signaling.

INPP5D

INPP5D

Inositol

INPP5D negatively regulates

polyphosphate-5-

myeloid cell proliferation and

phosphatase,

145

survival.

Myocyte enhancer

MEF2C

factor 2C

formation, and its mutation is

Not known

kDa MEF2C

associated

regulates

with

synapse

Not known

mental

retardation. NME8

NME/NM23 family

NME8 is implicated in ciliary

member 8

functions and its mutation is

Not known

associated with primary ciliary dyskinesia.

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official journal of the Society for Neuroscience. 33, 13138-49. Zhuang, X., Wang, H., Lam, S.K., Gao, C., Wang, X., Cai, Y., Jiang, L., 2013. A BAR-domain protein SH3P2, which binds to phosphatidylinositol 3-phosphate and ATG8, regulates autophagosome formation in Arabidopsis. Plant Cell. 25, 4596-615. Highlights 

The autophagy-related features and roles of AD-associated genes are reviewed.

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APP, A, ADAM10, and tau are autophagy substrates.

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Presenilin, PICALM, clusterin, CD2AP, and ephrin A1 regulate autophagy through various mechanisms.

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