Table 1. Microglial roles for AD risk genes identified in genome-wide associations
Gene/proteinMolecular functionActivities in microglial biology and AD
Lipid transport
APOEMajor apolipoprotein in brain HDL-like particlesConveys Aβ to lipoprotein receptors for clearance. Microglial Apoe expression induced in neurodegenerative models.
CLU/apoJAnother apolipoprotein in brain, usually in separate lipoparticles from apoEPromotes Aβ solubility. Conveys Aβ to lipoprotein receptors for clearance (DeMattos et al., 2004).
Transmembrane proteins
SORL1Receptor for vesicular sorting of lipoproteins and various receptorsBinds Aβ and directs it to lysosome (Caglayan et al., 2014). Rare variant in this domain = familial AD. High microglial expression in human.
ABCA7ATP-binding cassette transporter; multipass transmembrane protein transports lipidsLocalizes to phagocytic cup (Jehle et al., 2006); presumed role in membrane remodeling. Impaired Aβ phagocytosis in Abca7-null mice (Fu et al., 2016).
TREM2Binds anionic/lipophilic ligands; triggers DAP12 ITAM to recruit kinase SykImplicated in cell viability, chemotaxis, and phagocytosis. Disease mutations impair interactions with apoE and apoJ.
CD33Binds sialylated ligands; phosphorylated ITIM recruits phosphatase SHP-1Protective allele reduces surface CD33 levels and enhances Aβ uptake. AD association not replicated in meta-analysis.
MS4A6AFour-pass transmembrane protein in MS4A family; function unknownLikely involved in microglial receptor complex, like MS4A1 (CD20) in B cells and MS4A2 (FCER1B) in basophils/mast cells
CR1Complement receptor 1; binds C1q and C3b/C4bRecognizes opsonized targets. Inactivates C3b/C4b. Variant with extra C3b/C4b-binding domain increases AD risk (Brouwers et al., 2012).
EPHA1Receptor tyrosine kinase for ephrin-A class ligandsStimulates Pyk2 phosphorylation and migration in T lymphocytes (Aasheim et al., 2005). Not yet studied in microglia.
HLA-DRB1/5Major histocompatibility complex class II protein for extracellular antigen presentationMay serve as intracellular adaptors during the innate immune response (Liu et al., 2011)
IL1RAPCoreceptor with IL1R1 for IL-1 signalingEnables proinflammatory signal transduction that may mitigate plaque pathology but exacerbate Tau pathology (Ghosh et al., 2013)
Membrane and cytoskeletal dynamics
INPP5D/SHIP1SH3-containing inositol phosphatase, converts phosphatidylinositol (3,4,5)-trisphosphate to phosphatidylinositol (3,4)-bisphosphateInteracts with DAP12, opposes PI3K recruitment, modulates receptor endocytosis, and curbs phagocytosis in macrophages
PLCG2Phospholipase activity cleaves phosphatidylinositol (4,5)-bisphosphate into IP3 and DAG second messengersActs downstream of SYK during ITAM signaling. IP3 and DAG effect calcium and PKC signaling.
CD2APAdaptor protein between membrane proteins and actin cytoskeletonInteractions 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.
BIN1Involved in membrane curvature and dynamin interactionRIN3 interaction (Kajiho et al., 2003) suggests role in microglia endocytosis. Also implicated in neuronal APP trafficking and tau propagation.
RIN3-SLC24A4RIN3: a guanine nucleotide exchange factor for Rab5 and Rab31RIN3: interacts with BIN1 and CD2AP. Functions in the early endocytic pathway (Kajiho et al., 2011).
PICALMPhosphatidylinositol-binding protein recruits clathrin and AP2 for vesicle assemblyPossible role in microglial endocytosis. Also implicated in neuronal APP trafficking and Aβ efflux via blood–brain barrier transcytosis.
PTK2B/Pyk2Non–receptor tyrosine kinase; homologue of focal adhesion kinaseActivated in microglia by fibrillar Aβ (Combs et al., 1999). Involved in chemotactic polarization and migration of macrophages (Okigaki et al., 2003).
CASS4Scaffold protein associated with focal adhesion kinases FAK, Pyk2Largely unstudied. Functions inferred by homology with p130Cas family.
ABI3Component of the Abi/WAVE complex involved in actin polymerization (Sekino et al., 2015)Probably involved in microglial motility and/or phagocytosis
FERMT2Adaptor between membrane and actin cytoskeleton at extracellular matrix adhesion sitesNot expressed in microglia; no conjectured role in microglial function. Implicated in APP trafficking.
Transcription factors
SPI1/PU.1Important for myeloid and B cell lineagesOriginally identified SNP was intronic rs10838725 in CELF1 gene. Protective SPI1 SNP = reduced PU.1 levels.
MEF2CWidely studied in muscle cells and neuronsMicroglial expression and calcium-dependent activation mechanisms (Lynch et al., 2005) suggest possible role downstream of TREM2.
Other
ZCWPW1Presumed epigenetic regulator through its chromatin-binding domainsSNPs across ∼10 genes show AD association; causal gene unknown. Neighboring genes encode paired immune receptors.
NME8Encodes protein with thioredoxin and nucleoside diphosphate kinase domainsUnknown 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.