Table 1. Microglial roles for AD risk... | Rockefeller University Press

Table 1.

Microglial roles for AD risk genes identified in genome-wide associations

Gene/protein	Molecular function	Activities in microglial biology and AD
Lipid transport
APOE	Major apolipoprotein in brain HDL-like particles	Conveys Aβ to lipoprotein receptors for clearance. Microglial Apoe expression induced in neurodegenerative models.
CLU/apoJ	Another apolipoprotein in brain, usually in separate lipoparticles from apoE	Promotes Aβ solubility. Conveys Aβ to lipoprotein receptors for clearance (DeMattos et al., 2004).
Transmembrane proteins
SORL1	Receptor for vesicular sorting of lipoproteins and various receptors	Binds Aβ and directs it to lysosome (Caglayan et al., 2014). Rare variant in this domain = familial AD. High microglial expression in human.
ABCA7	ATP-binding cassette transporter; multipass transmembrane protein transports lipids	Localizes to phagocytic cup (Jehle et al., 2006); presumed role in membrane remodeling. Impaired Aβ phagocytosis in Abca7-null mice (Fu et al., 2016).
TREM2	Binds anionic/lipophilic ligands; triggers DAP12 ITAM to recruit kinase Syk	Implicated in cell viability, chemotaxis, and phagocytosis. Disease mutations impair interactions with apoE and apoJ.
CD33	Binds sialylated ligands; phosphorylated ITIM recruits phosphatase SHP-1	Protective allele reduces surface CD33 levels and enhances Aβ uptake. AD association not replicated in meta-analysis.
MS4A6A	Four-pass transmembrane protein in MS4A family; function unknown	Likely involved in microglial receptor complex, like MS4A1 (CD20) in B cells and MS4A2 (FCER1B) in basophils/mast cells
CR1	Complement receptor 1; binds C1q and C3b/C4b	Recognizes opsonized targets. Inactivates C3b/C4b. Variant with extra C3b/C4b-binding domain increases AD risk (Brouwers et al., 2012).
EPHA1	Receptor tyrosine kinase for ephrin-A class ligands	Stimulates Pyk2 phosphorylation and migration in T lymphocytes (Aasheim et al., 2005). Not yet studied in microglia.
HLA-DRB1/5	Major histocompatibility complex class II protein for extracellular antigen presentation	May serve as intracellular adaptors during the innate immune response (Liu et al., 2011)
IL1RAP	Coreceptor with IL1R1 for IL-1 signaling	Enables proinflammatory signal transduction that may mitigate plaque pathology but exacerbate Tau pathology (Ghosh et al., 2013)
Membrane and cytoskeletal dynamics
INPP5D/SHIP1	SH3-containing inositol phosphatase, converts phosphatidylinositol (3,4,5)-trisphosphate to phosphatidylinositol (3,4)-bisphosphate	Interacts with DAP12, opposes PI3K recruitment, modulates receptor endocytosis, and curbs phagocytosis in macrophages
PLCG2	Phospholipase activity cleaves phosphatidylinositol (4,5)-bisphosphate into IP3 and DAG second messengers	Acts downstream of SYK during ITAM signaling. IP3 and DAG effect calcium and PKC signaling.
CD2AP	Adaptor protein between membrane proteins and actin cytoskeleton	Interactions with SHIP1 and RIN3 (Bao et al., 2012; Rouka et al., 2015) suggest role in microglia endocytosis. Also implicated in neuronal APP trafficking and tau propagation.
BIN1	Involved in membrane curvature and dynamin interaction	RIN3 interaction (Kajiho et al., 2003) suggests role in microglia endocytosis. Also implicated in neuronal APP trafficking and tau propagation.
RIN3-SLC24A4	RIN3: a guanine nucleotide exchange factor for Rab5 and Rab31	RIN3: interacts with BIN1 and CD2AP. Functions in the early endocytic pathway (Kajiho et al., 2011).
PICALM	Phosphatidylinositol-binding protein recruits clathrin and AP2 for vesicle assembly	Possible role in microglial endocytosis. Also implicated in neuronal APP trafficking and Aβ efflux via blood–brain barrier transcytosis.
PTK2B/Pyk2	Non–receptor tyrosine kinase; homologue of focal adhesion kinase	Activated in microglia by fibrillar Aβ (Combs et al., 1999). Involved in chemotactic polarization and migration of macrophages (Okigaki et al., 2003).
CASS4	Scaffold protein associated with focal adhesion kinases FAK, Pyk2	Largely unstudied. Functions inferred by homology with p130Cas family.
ABI3	Component of the Abi/WAVE complex involved in actin polymerization (Sekino et al., 2015)	Probably involved in microglial motility and/or phagocytosis
FERMT2	Adaptor between membrane and actin cytoskeleton at extracellular matrix adhesion sites	Not expressed in microglia; no conjectured role in microglial function. Implicated in APP trafficking.
Transcription factors
SPI1/PU.1	Important for myeloid and B cell lineages	Originally identified SNP was intronic rs10838725 in CELF1 gene. Protective SPI1 SNP = reduced PU.1 levels.
MEF2C	Widely studied in muscle cells and neurons	Microglial expression and calcium-dependent activation mechanisms (Lynch et al., 2005) suggest possible role downstream of TREM2.
Other
ZCWPW1	Presumed epigenetic regulator through its chromatin-binding domains	SNPs across ∼10 genes show AD association; causal gene unknown. Neighboring genes encode paired immune receptors.
NME8	Encodes protein with thioredoxin and nucleoside diphosphate kinase domains	Unknown cellular function

Gene/protein	Molecular function	Activities in microglial biology and AD
Lipid transport
APOE	Major apolipoprotein in brain HDL-like particles	Conveys Aβ to lipoprotein receptors for clearance. Microglial Apoe expression induced in neurodegenerative models.
CLU/apoJ	Another apolipoprotein in brain, usually in separate lipoparticles from apoE	Promotes Aβ solubility. Conveys Aβ to lipoprotein receptors for clearance (DeMattos et al., 2004).
Transmembrane proteins
SORL1	Receptor for vesicular sorting of lipoproteins and various receptors	Binds Aβ and directs it to lysosome (Caglayan et al., 2014). Rare variant in this domain = familial AD. High microglial expression in human.
ABCA7	ATP-binding cassette transporter; multipass transmembrane protein transports lipids	Localizes to phagocytic cup (Jehle et al., 2006); presumed role in membrane remodeling. Impaired Aβ phagocytosis in Abca7-null mice (Fu et al., 2016).
TREM2	Binds anionic/lipophilic ligands; triggers DAP12 ITAM to recruit kinase Syk	Implicated in cell viability, chemotaxis, and phagocytosis. Disease mutations impair interactions with apoE and apoJ.
CD33	Binds sialylated ligands; phosphorylated ITIM recruits phosphatase SHP-1	Protective allele reduces surface CD33 levels and enhances Aβ uptake. AD association not replicated in meta-analysis.
MS4A6A	Four-pass transmembrane protein in MS4A family; function unknown	Likely involved in microglial receptor complex, like MS4A1 (CD20) in B cells and MS4A2 (FCER1B) in basophils/mast cells
CR1	Complement receptor 1; binds C1q and C3b/C4b	Recognizes opsonized targets. Inactivates C3b/C4b. Variant with extra C3b/C4b-binding domain increases AD risk (Brouwers et al., 2012).
EPHA1	Receptor tyrosine kinase for ephrin-A class ligands	Stimulates Pyk2 phosphorylation and migration in T lymphocytes (Aasheim et al., 2005). Not yet studied in microglia.
HLA-DRB1/5	Major histocompatibility complex class II protein for extracellular antigen presentation	May serve as intracellular adaptors during the innate immune response (Liu et al., 2011)
IL1RAP	Coreceptor with IL1R1 for IL-1 signaling	Enables proinflammatory signal transduction that may mitigate plaque pathology but exacerbate Tau pathology (Ghosh et al., 2013)
Membrane and cytoskeletal dynamics
INPP5D/SHIP1	SH3-containing inositol phosphatase, converts phosphatidylinositol (3,4,5)-trisphosphate to phosphatidylinositol (3,4)-bisphosphate	Interacts with DAP12, opposes PI3K recruitment, modulates receptor endocytosis, and curbs phagocytosis in macrophages
PLCG2	Phospholipase activity cleaves phosphatidylinositol (4,5)-bisphosphate into IP3 and DAG second messengers	Acts downstream of SYK during ITAM signaling. IP3 and DAG effect calcium and PKC signaling.
CD2AP	Adaptor protein between membrane proteins and actin cytoskeleton	Interactions with SHIP1 and RIN3 (Bao et al., 2012; Rouka et al., 2015) suggest role in microglia endocytosis. Also implicated in neuronal APP trafficking and tau propagation.
BIN1	Involved in membrane curvature and dynamin interaction	RIN3 interaction (Kajiho et al., 2003) suggests role in microglia endocytosis. Also implicated in neuronal APP trafficking and tau propagation.
RIN3-SLC24A4	RIN3: a guanine nucleotide exchange factor for Rab5 and Rab31	RIN3: interacts with BIN1 and CD2AP. Functions in the early endocytic pathway (Kajiho et al., 2011).
PICALM	Phosphatidylinositol-binding protein recruits clathrin and AP2 for vesicle assembly	Possible role in microglial endocytosis. Also implicated in neuronal APP trafficking and Aβ efflux via blood–brain barrier transcytosis.
PTK2B/Pyk2	Non–receptor tyrosine kinase; homologue of focal adhesion kinase	Activated in microglia by fibrillar Aβ (Combs et al., 1999). Involved in chemotactic polarization and migration of macrophages (Okigaki et al., 2003).
CASS4	Scaffold protein associated with focal adhesion kinases FAK, Pyk2	Largely unstudied. Functions inferred by homology with p130Cas family.
ABI3	Component of the Abi/WAVE complex involved in actin polymerization (Sekino et al., 2015)	Probably involved in microglial motility and/or phagocytosis
FERMT2	Adaptor between membrane and actin cytoskeleton at extracellular matrix adhesion sites	Not expressed in microglia; no conjectured role in microglial function. Implicated in APP trafficking.
Transcription factors
SPI1/PU.1	Important for myeloid and B cell lineages	Originally identified SNP was intronic rs10838725 in CELF1 gene. Protective SPI1 SNP = reduced PU.1 levels.
MEF2C	Widely studied in muscle cells and neurons	Microglial expression and calcium-dependent activation mechanisms (Lynch et al., 2005) suggest possible role downstream of TREM2.
Other
ZCWPW1	Presumed epigenetic regulator through its chromatin-binding domains	SNPs across ∼10 genes show AD association; causal gene unknown. Neighboring genes encode paired immune receptors.
NME8	Encodes protein with thioredoxin and nucleoside diphosphate kinase domains	Unknown cellular function

AD-associated genes are described in terms of microglial functions known or speculated to govern AD pathogenesis. References are provided only for certain material not mentioned elsewhere in the text.

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