| 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.