Alzheimer’s disease (AD) is a debilitating age-related neurodegenerative condition. Unbiased genetic studies have implicated a central role for microglia, the resident innate immune cells of the central nervous system, in AD pathogenesis. On-going efforts are clarifying the biology underlying these associations and the microglial pathways that are dysfunctional in AD. Several genetic risk factors converge to decrease the function of activating microglial receptors and increase the function of inhibitory receptors, resulting in a seemingly dampened microglial phenotype in AD. Moreover, many of these microglial proteins that are genetically associated with AD appear to interact and share pathways or regulatory mechanisms, presenting several points of convergence that may be strategic targets for therapeutic intervention. Here, we review some of these studies and their implications for microglial participation in AD pathogenesis.
AkiyamaHBargerSBarnumSBradtBBauerJColeGM, and others. 2000. Inflammation and Alzheimer’s disease. Neurobiol Aging21(3):383–421.
2.
Alector-Inc. 2020. A phase 2 study to evaluate efficacy and safety of AL002 in participants with early Alzheimer’s disease (INVOKE-2). Available from: https://clinicaltrials.gov/ct2/show/NCT04592874
3.
AlliotFGodinIPessacB.1999. Microglia derive from progenitors, originating from the yolk sac, and which proliferate in the brain. Brain Res Dev Brain Res117(2):145–52.
4.
AllnuttMAJohnsonKBennettDAConnorSMTroncosoJCPletnikovaO, and others. 2020. Human herpesvirus 6 detection in Alzheimer’s disease cases and controls across multiple cohorts. Neuron105(6):1027–35.e1022.
5.
AlzheimerA. 1907. Uber eine eigenartige erkrankung der hirnrinde. Zentralbl Nervenh Psych18:177–9.
6.
AlzheimerAStelzmannRASchnitzleinHNMurtaghFR. 1995. An English translation of Alzheimer’s 1907 paper, “Uber eine eigenartige erkankung der hirnrinde”. Clin Anat8(6):429–31.
AndreoneBJPrzybylaLLlapashticaCRanaADavisSSvan LengerichB, and others. 2020. Alzheimer’s-associated plcγ2 is a signaling node required for both trem2 function and the inflammatory response in human microglia. Nat Neurosci23(8):927–38.
9.
AndrewsSJFulton-HowardBGoateA.2020. Interpretation of risk loci from genome-wide association studies of Alzheimer’s disease. Lancet Neurol19(4):326–35.
10.
ArtsRJWJoostenLABMeerJWMNeteaMG. 2012. Trem-1: intracellular signaling pathways and interaction with pattern recognition receptors. J Leukoc Biol93(2):209–15.
11.
AskewKGomez-NicolaD.2018. A story of birth and death: insights into the formation and dynamics of the microglial population. Brain Behav Immun69:9–17.
12.
AvagyanHGoldensonBTseEMasoumiAPorterVWiedau-PazosM, and others. 2009. Immune blood biomarkers of Alzheimer disease patients. J Neuroimmunol210(1–2):67–72.
13.
BaeYSLeeHYJungYSLeeMSuhPG. 2017. Phospholipase cγ in toll-like receptor-mediated inflammation and innate immunity. Adv Biol Regul63:92–7.
14.
BarcellosLFSawcerSRamsayPPBaranziniSEThomsonGBriggsF, and others. 2006. Heterogeneity at the hla-drb1 locus and risk for multiple sclerosis. Hum Mol Genet15(18):2813–24.
15.
BatemanRJXiongCBenzingerTLSFaganAMGoateAFoxNC, and others. 2012. Clinical and biomarker changes in dominantly inherited Alzheimer’s disease. N Engl J Med367(9):795–804.
16.
BertramLLangeCMullinKParkinsonMHsiaoMHoganMF, and others. 2008. Genome-wide association analysis reveals putative Alzheimer’s disease susceptibility loci in addition to apoe. Am J Hum Genet83(5):623–32.
17.
BhattacherjeeARodriguesEJungJLuzentales-SimpsonMEnterinaJRGalleguillosD, and others. 2019. Repression of phagocytosis by human cd33 is not conserved with mouse cd33. Commun Biol2:450.
18.
BleharskiJRKiesslerVBuonsantiCSielingPAStengerSColonnaM.2003. A role for triggering receptor expressed on myeloid cells-1 in host defense during the early-induced and adaptive phases of the immune response. J Immunol170(7):3812–8.
19.
BodgerMPHartDNJ. 1998. Molecular cloning and functional analysis of the cd33 promoter. Br J Haematol102(4):986–95.
20.
BouchonAHernández-MunainCCellaMColonnaM.2001. A dap12-mediated pathway regulates expression of cc chemokine receptor 7 and maturation of human dendritic cells. J Exp Med194(8):1111–22.
21.
BouretteRPMylesGMChoiJLRohrschneiderLR. 1997. Sequential activation of phoshatidylinositol 3-kinase and phospholipase c-gamma2 by the M-CSF receptor is necessary for differentiation signaling. EMBO J. 16(19):5880–93.
22.
BradshawEMChibnikLBKeenanBTOttoboniLRajTTangA, and others. 2013. CD33 Alzheimer’s disease locus: altered monocyte function and amyloid biology. Nat Neurosci16(7):848–50.
23.
BraidyNGrantRSachdevPS. 2018. Nicotinamide adenine dinucleotide and its related precursors for the treatment of Alzheimer’s disease. Curr Opin Psychiatry31(2):160–6.
24.
BrookmeyerREvansDAHebertLLangaKMHeeringaSGPlassmanBL. 2011. National estimates of the prevalence of Alzheimer’s disease in the United States. Alzheimers Dement7(1):61–73.
25.
CaiMChenQChenCLiuXHouJZengC.2013. Activation of triggering receptor expressed on myeloid cells-1 protects monocyte from apoptosis through regulation of myeloid cell leukemia-1. Anesthesiology118(5):1140–9.
26.
CaoHCrockerPR. 2011. Evolution of CD33-related siglecs: regulating host immune functions and escaping pathogen exploitation?Immunology. 132(1):18–26.
27.
ChaeJJParkYHParkCHwangIYHoffmannPKehrlJH. 2015. Connecting two pathways through Ca2+ signaling: Nlrp3 inflammasome activation induced by a hypermorphic PLCG2 mutation. Arthritis Rheumatol67(2):563–7.
28.
ChanGWhiteCCWinnPACimpeanMReplogleJMGlickLR, and others. 2015. CD33 modulates TREM2: convergence of Alzheimer loci. Nat Neurosci18(11):1556–8.
29.
ChenXEksiogluEAZhouJZhangLDjeuJFortenberyN, and others. 2013. Induction of myelodysplasia by myeloid-derived suppressor cells. J Clin Invest123(11):4595–611.
30.
ChiangCYVeckmanVLimmerKDavidM.2012. Phospholipase cγ-2 and intracellular calcium are required for lipopolysaccharide-induced toll-like receptor 4 (TLR4) endocytosis and interferon regulatory factor 3 (IRF3) activation. J Biol Chem287(6):3704–9.
31.
ChituVStanleyER. 2006. Colony-stimulating factor-1 in immunity and inflammation. Curr Opin Immunol18(1):39–48.
32.
ClaesCVan Den DaeleJBoonRSchoutedenSColomboAMonasorLS, and others. 2019. Human stem cell-derived monocytes and microglia-like cells reveal impaired amyloid plaque clearance upon heterozygous or homozygous loss of TREM2. Alzheimers Dement15(3):453–64.
33.
ColonnaM. 2003. Trems in the immune system and beyond. Nat Rev Immunol3(6):445–53.
34.
CoppéJPDesprezPYKrtolicaACampisiJ.2010. The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu Rev Pathol5:99–118.
35.
CrockerPRPaulsonJCVarkiA.2007. Siglecs and their roles in the immune system. Nat Rev Immunol7(4):255–66.
36.
CrockerPRRedelinghuysP.2008. Siglecs as positive and negative regulators of the immune system. Biochem Soc Trans36(6):1467–71.
37.
DaiXMRyanGRHapelAJDominguezMGRussellRGKappS, and others. 2002. Targeted disruption of the mouse colony-stimulating factor 1 receptor gene results in osteopetrosis, mononuclear phagocyte deficiency, increased primitive progenitor cell frequencies, and reproductive defects. Blood99(1):111–20.
38.
DakicAMetcalfDDi RagoLMifsudSWuLNuttSL. 2005. Pu.1 regulates the commitment of adult hematopoietic progenitors and restricts granulopoiesis. J Exp Med201(9):1487–502.
39.
DamaniMRZhaoLFontainhasAMAmaralJFarissRNWongWT. 2011. Age-related alterations in the dynamic behavior of microglia. Aging Cell10(2):263–76.
40.
de CraenAJGusseklooJVrijsenBWestendorpRG. 2005. Meta-analysis of nonsteroidal antiinflammatory drug use and risk of dementia. Am J Epidemiol161(2):114–20.
41.
de RojasIMoreno-GrauSTesiNGrenier-BoleyBAndradeVJansenI, and others. 2020. Common variants in Alzheimer’s disease: novel association of six genetic variants with ad and risk stratification by polygenic risk scores. medRxiv. https://doi.org/10.1101/19012021
42.
Del GiudiceGGoronzyJJGrubeck-LoebensteinBLambertPHMrkvanTStoddardJJ, and others. 2018. Fighting against a protean enemy: immunosenescence, vaccines, and healthy aging. NPJ Aging Mech Dis4:1.
43.
DemarestTGBabbarMOkurMNDanXCroteauDLFakouriNB, and others. 2019. NAD+ metabolism in aging and cancer. Annu Rev Cancer Biol3(1):105–30.
44.
DominySSLynchCErminiFBenedykMMarczykAKonradiA, and others. 2019. Porphyromonas gingivalis in Alzheimer’s disease brains: evidence for disease causation and treatment with small-molecule inhibitors. Sci Adv5(1):eaau3333.
45.
DowerKEllisDKSarafKJelinskySALinLL. 2008. Innate immune responses to trem-1 activation: overlap, divergence, and positive and negative cross-talk with bacterial lipopolysaccharide. J Immunol180(5):3520–34.
46.
DreganACharltonJChowienczykPGullifordMC. 2014. Chronic inflammatory disorders and risk of type 2 diabetes mellitus, coronary heart disease, and stroke: a population-based cohort study. Circulation130(10):837–44.
47.
DuyckaertsCDelatourBPotierMC. 2009. Classification and basic pathology of Alzheimer disease. Acta Neuropathol118(1):5–36.
48.
EffrosRB. 2016. The silent war of CMV in aging and HIV infection. Mech Ageing Dev158:46–52.
49.
EimerWAVijaya KumarDKNavalpur ShanmugamNKRodriguezASMitchellTWashicoskyKJ, and others. 2018. Alzheimer’s disease-associated β-amyloid is rapidly seeded by herpesviridae to protect against brain infection. Neuron99(1):56–63.e53.
EstusSShawBCDevanneyNKatsumataYPressEEFardoDW. 2019. Evaluation of CD33 as a genetic risk factor for Alzheimer’s disease. Acta Neuropathol138(2):187–99.
52.
FairweatherDPetriMACoronadoMJCooperLT. 2012. Autoimmune heart disease: role of sex hormones and autoantibodies in disease pathogenesis. Expert Rev Clin Immunol8(3):269–84.
53.
FialaMCribbsDHRosenthalMBernardG.2007. Phagocytosis of amyloid-beta and inflammation: two faces of innate immunity in Alzheimer’s disease. J Alzheimers Dis11(4):457–63.
54.
FialaMLinJRingmanJKermani-ArabVTsaoGPatelA, and others. 2005. Ineffective phagocytosis of amyloid-beta by macrophages of Alzheimer’s disease patients. J Alzheimers Dis7(3):221–32.
55.
FriedmanAD. 2007. Transcriptional control of granulocyte and monocyte development. Oncogene26(47):6816–28.
56.
FurmanDCampisiJVerdinECarrera-BastosPTargSFranceschiC, and others. 2019. Chronic inflammation in the etiology of disease across the life span. Nat Med25(12):1822–32.
57.
GibotSMassinFMarcouMTaylorVStidwillRWilsonP, and others. 2007. TREM-1 promotes survival during septic shock in mice. Eur J Immunol37(2):456–66.
58.
GinhouxFGreterMLeboeufMNandiSSeePGokhanS, and others. 2010. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science330(6005):841–5.
59.
GinhouxFLimSHoeffelGLowDHuberT.2013. Origin and differentiation of microglia. Front Cell Neurosci7:45.
60.
GraeberMBKöselSEgenspergerRBanatiRBMüllerUBiseK, and others. 1997. Rediscovery of the case described by Alois Alzheimer in 1911: historical, histological and molecular genetic analysis. Neurogenetics1(1):73–80.
61.
GratuzeMLeynsCESauerbeckADSt-PierreMKXiongMKimN, and others. 2020. Impact of TREM2R47H variant on tau pathology-induced gliosis and neurodegeneration. J Clin Invest130(9):4954–68.
62.
GreenfieldALHauserSL. 2018. B-cell therapy for multiple sclerosis: entering an era. Ann Neurol83(1):13–26.
63.
GriciucAPatelSFedericoANChoiSHInnesBJOramMK, and others. 2019. TREM2 acts downstream of CD33 in modulating microglial pathology in Alzheimer’s disease. Neuron103(5):820–35.e827.
64.
GriciucASerrano-PozoAParrado AntonioRLesinski AndreaNAsselin CarolineNMullinK, and others. 2013. Alzheimer’s disease risk gene CD33 inhibits microglial uptake of amyloid beta. Neuron78(4):631–43.
65.
GuerreiroRWojtasABrasJCarrasquilloMRogaevaEMajounieE, and others. 2013. TREM2 variants in Alzheimer’s disease. N Engl J Med368(2):117–27.
66.
HamermanJAJarjouraJRHumphreyMBNakamuraMCSeamanWELanierLL. 2006. Cutting edge: inhibition of TLR and FCR responses in macrophages by triggering receptor expressed on myeloid cells (TREM)-2 and DAP12. J Immunol177(4):2051–5.
67.
HammondTRRobintonDStevensB.2018. Microglia and the brain: complementary partners in development and disease. Annu Rev Cell Dev Biol34:523–44.
68.
HamzaTHZabetianCPTenesaALaederachAMontimurroJYearoutD, and others. 2010. Common genetic variation in the HLA region is associated with late-onset sporadic Parkinson’s disease. Nat Genet42(9):781–5.
69.
HanischUKKettenmannH.2007. Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci10(11):1387–94.
70.
HaroldDAbrahamRHollingworthPSimsRGerrishAHamshereML, and others. 2009. Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer’s disease. Nat Genet41(10):1088–93.
71.
HefendehlJKNeherJJSühsRBKohsakaSSkodrasAJuckerM.2014. Homeostatic and injury-induced microglia behavior in the aging brain. Aging Cell13(1):60–9.
72.
HickmanSEAllisonEKEl KhouryJ.2008. Microglial dysfunction and defective β-amyloid clearance pathways in aging Alzheimer’s disease mice. J Neurosci28(33):8354.
73.
HoeffelGWangYGreterMSeePTeoPMalleretB, and others. 2012. Adult Langerhans cells derive predominantly from embryonic fetal liver monocytes with a minor contribution of yolk sac-derived macrophages. J Exp Med209(6):1167–81.
74.
HollingworthPHaroldDJonesLOwenMJWilliamsJ.2011a. Alzheimer’s disease genetics: current knowledge and future challenges. Int J Geriatr Psychiatry26(8):793–802.
75.
HollingworthPHaroldDSimsRGerrishALambertJCCarrasquilloMM, and others. 2011b. Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer’s disease. Nat Genet43(5):429–35.
76.
HommesTJHoogendijkAJDessingMCVeerCVTFlorquinSColonnaM, and others. 2014. Triggering receptor expressed on myeloid cells-1 (TREM-1) improves host defence in pneumococcal pneumonia. J Pathol233(4):357–67.
77.
HuangKLMarcoraEPimenovaAANarzoAFDKapoorMJinSC, and others. 2017. A common haplotype lowers PU.1 expression in myeloid cells and delays onset of Alzheimer’s disease. Nat Neurosci20(8):1052–61.
78.
in t’ VeldBARuitenbergAHofmanALaunerLJvan DuijnCMStijnenT, and others. 2001. Nonsteroidal antiinflammatory drugs and the risk of Alzheimer’s disease. N Engl J Med345(21):1515–21.
79.
IshidaAAkitaKMoriYTanidaSTodaMInoueM, and others. 2014. Negative regulation of toll-like receptor-4 signaling through the binding of glycosylphosphatidylinositol-anchored glycoprotein, CD14, with the sialic acid-binding lectin, CD33. J Biol Chem289(36):25341–50.
80.
ItagakiSMcGeerPLAkiyamaH.1988. Presence of T-cytotoxic suppressor and leucocyte common antigen positive cells in Alzheimer’s disease brain tissue. Neurosci Lett91(3):259–64.
81.
JackCRJrBennettDABlennowKCarrilloMCDunnBHaeberleinSB, and others. 2018. NIA-AA research framework: toward a biological definition of Alzheimer’s disease. Alzheimers Dement14(4):535–62.
82.
JansenIESavageJEWatanabeKBryoisJWilliamsDMSteinbergS, and others. 2019. Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer’s disease risk. Nat Genet51(3):404–13.
83.
JayTRHirschAMBroihierMLMillerCMNeilsonLERansohoffRM, and others. 2017. Disease progression-dependent effects of TREM2 deficiency in a mouse model of Alzheimer’s disease. J Neurosci37(3):637.
84.
JiangTZhangYDGaoQZhouJSZhuXCLuH, and others. 2016. TREM1 facilitates microglial phagocytosis of amyloid beta. Acta Neuropathol132(5):667–83.
85.
JonssonTStefanssonHSteinbergSJonsdottirIJonssonPVSnaedalJ, and others. 2013. Variant of TREM2 associated with the risk of Alzheimer’s disease. N Engl J Med368(2):107–16.
86.
JoseSSBendickovaKKepakTKrenovaZFricJ.2017. Chronic inflammation in immune aging: role of pattern recognition receptor crosstalk with the telomere complex?Front Immunol8:1078–8.
87.
KawaboriMKacimiRKauppinenTCalosingCKimJYHsiehCL, and others. 2015. Triggering receptor expressed on myeloid cells 2 (TREM2) deficiency attenuates phagocytic activities of microglia and exacerbates ischemic damage in experimental stroke. J Neurosci35(8):3384–96.
88.
Keren-ShaulHSpinradAWeinerAMatcovitch-NatanODvir-SzternfeldRUllandTK, and others. 2017. A unique microglia type associated with restricting development of Alzheimer’s disease. Cell169(7):1276–90.e1217.
89.
KleinbergerGYamanishiYSuárez-CalvetMCzirrELohmannECuyversE, and others. 2014. TREM2 mutations implicated in neurodegeneration impair cell surface transport and phagocytosis. Sci Transl Med6(243):243ra286.
90.
KoberDLAlexander-BrettJMKarchCMCruchagaCColonnaMHoltzmanMJ, and others. 2016. Neurodegenerative disease mutations in Trem2 reveal a functional surface and distinct loss-of-function mechanisms. Elife5.
91.
KonishiHKiyamaH.2018. Microglial TREM2/DAP12 signaling: a double-edged sword in neural diseases. Front Cell Neurosci12:206.
92.
KronenbergGUhlemannRSchönerJWegnerSBoujonVDeigendeschN, and others. 2017. Repression of telomere-associated genes by microglia activation in neuropsychiatric disease. Eur Arch Psychiatry Clin Neurosci267(5):473–7.
93.
KumarDKChoiSHWashicoskyKJEimerWATuckerSGhofraniJ, and others. 2016. Amyloid-β peptide protects against microbial infection in mouse and worm models of Alzheimer’s disease. Sci Transl Med8(340):340ra372.
94.
KunkleBWGrenier-BoleyBSimsRBisJCDamotteVNajAC, and others. 2019. Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates aβ, tau, immunity and lipid processing. Nat Genet51(3):414–30.
95.
LaglerHSharifOHaslingerIMattUStichKFurtnerT, and others. 2009. TREM-1 activation alters the dynamics of pulmonary IRAK-M expression in vivo and improves host defense during pneumococcal pneumonia. J Immunol Baltim Md 1950183(3):2027–36.
96.
LajauniasFDayerJMChizzoliniC.2005. Constitutive repressor activity of CD33 on human monocytes requires sialic acid recognition and phosphoinositide 3-kinase-mediated intracellular signaling. Eur J Immunol35(1):243–51.
97.
LambertJCHeathSEvenGCampionDSleegersKHiltunenM, and others. 2009. Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer’s disease. Nat Genet41(10):1094–9.
98.
LambertJCIbrahim-VerbaasCAHaroldDNajACSimsRBellenguezC, and others. 2013. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease. Nat Genet45(12):1452–8.
99.
LanierLL. 2009. DAP10- and DAP12-associated receptors in innate immunity. Immunol Rev227(1):150–60.
100.
LautrupSSinclairDAMattsonMPFangEF. 2019. NAD(+) in brain aging and neurodegenerative disorders. Cell Metab30(4):630–55.
101.
LeeCYDDaggettAGuXJiangLLLangfelderPLiX, and others. 2018. Elevated TREM2 gene dosage reprograms microglia responsivity and ameliorates pathological phenotypes in Alzheimer’s disease models. Neuron97(5):1032–48.e1035.
102.
LeynsCEGUlrichJDFinnMBStewartFRKoscalLJRemolina SerranoJ, and others. 2017. TREM2 deficiency attenuates neuroinflammation and protects against neurodegeneration in a mouse model of tauopathy. Proc Natl Acad Sci U S A114(43):11524.
103.
LiHLiuCCZhengHHuangTY. 2018. Amyloid, tau, pathogen infection and antimicrobial protection in Alzheimer’s disease—conformist, nonconformist, and realistic prospects for ad pathogenesis. Transl Neurodegener7:34.
104.
LillCMRengmarkAPihlstrømLFoghIShatunovASleimanPM, and others. 2015. The role of TREM2 R47H as a risk factor for Alzheimer’s disease, frontotemporal lobar degeneration, amyotrophic lateral sclerosis, and Parkinson’s disease. Alzheimers Dement11(12):1407–16.
105.
LinHLeeEHestirKLeoCHuangMBoschE, and others. 2008. Discovery of a cytokine and its receptor by functional screening of the extracellular proteome. Science320(5877):807–11.
106.
LiuHLeoCChenXWongBRWilliamsLTLinH, and others. 2012. The mechanism of shared but distinct CSF-1R signaling by the non-homologous cytokines IL-34 and CSF-1. Biochim Biophys Acta1824(7):938–45.
107.
LuoJElwoodFBritschgiMVilledaSZhangHDingZ, and others. 2013. Colony-stimulating factor 1 receptor (CSF1R) signaling in injured neurons facilitates protection and survival. J Exp Med210(1):157–72.
108.
MaDDoiYJinSLiESonobeYTakeuchiH, and others. 2012. TGF-β induced by interleukin-34-stimulated microglia regulates microglial proliferation and attenuates oligomeric amyloid β neurotoxicity. Neurosci Lett529(1):86–91.
109.
MagnoLLessardCBMartinsMLangVCruzPAsiY, and others. 2019. Alzheimer’s disease phospholipase C-gamma-2 (PLCG2) protective variant is a functional hypermorph. Alzheimers Res Ther11(1):16.
110.
MalikMSimpsonJFParikhIWilfredBRFardoDWNelsonPT, and others. 2013. CD33 Alzheimer’s risk-altering polymorphism, CD33 expression, and exon 2 splicing. J Neurosci33(33):13320–5.
111.
MaragakisNJRothsteinJD. 2006. Mechanisms of disease: astrocytes in neurodegenerative disease. Nat Clin Pract Neurol2(12):679–89.
112.
MarioniREHarrisSEZhangQMcRaeAFHagenaarsSPHillWD, and others. 2018. GWAS on family history of Alzheimer’s disease. Transl Psychiatry8(1):99.
113.
MastroeniDNolzJSekarSDelvauxESerranoGCuyuganL, and others. 2017. Laser-captured microglia in the Alzheimer’s and Parkinson’s brain reveal unique regional expression profiles and suggest a potential role for hepatitis B in the Alzheimer’s brain. Neurobiol Aging63:12–21.
114.
MathysHAdaikkanCGaoFYoungJZManetEHembergM, and others. 2017. Temporal tracking of microglia activation in neurodegeneration at single-cell resolution. Cell Rep21(2):366–80.
115.
MawandaFWallaceR.2013. Can infections cause Alzheimer’s disease?Epidemiol Rev35(1):161–80.
116.
MawuenyegaKGSigurdsonWOvodVMunsellLKastenTMorrisJC, and others. 2010. Decreased clearance of CNS beta-amyloid in Alzheimer’s disease. Science330(6012):1774.
117.
McCarthyMM. 2017. Location, location, location: Microglia are where they live. Neuron95(2):233–5.
118.
MerliniMKirabaliTKulicLNitschRMFerrettiMT. 2018. Extravascular CD3+ T cells in brains of Alzheimer disease patients correlate with tau but not with amyloid pathology: an immunohistochemical study. Neurodegen Dis18(1):49–56.
119.
MeyerPFTremblay-MercierJLeoutsakosJMadjarCLafaille-MaignanMSavardM, and others. 2019. Intrepad: a randomized trial of naproxen to slow progress of presymptomatic Alzheimer disease. Neurology92(18):e2070–e2080.
120.
MinderjahnJSchmidtAFuchsASchillRRaithelJBabinaM, and others. 2020. Mechanisms governing the pioneering and redistribution capabilities of the non-classical pioneer PU.1. Nat Commun11(1):402.
121.
MisraMKDamotteVHollenbachJA. 2019. Structure-based selection of human metabolite binding P4 pocket of DRB1*15:01 and DRB1*15:03, with implications for multiple sclerosis. Genes Immun20(1):46–55.
122.
MizunoTDoiYMizoguchiHJinSNodaMSonobeY, and others. 2011. Interleukin-34 selectively enhances the neuroprotective effects of microglia to attenuate oligomeric amyloid-β neurotoxicity. Am J Pathol179(4):2016–27.
123.
MorrisJCEdlandSClarkCGalaskoDKossEMohsR, and others. 1993. The Consortium to Establish a Registry for Alzheimer’s Disease (CERAD): Part IV. Rates of cognitive change in the longitudinal assessment of probable Alzheimer’s disease. Neurology43(12):2457.
124.
MosherKIWyss-CorayT.2014. Microglial dysfunction in brain aging and Alzheimer’s disease. Biochem Pharmacol88(4):594–604.
125.
NajACJunGBeechamGWWangLSVardarajanBNBurosJ, and others. 2011. Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer’s disease. Nat Genet43(5):436–41.
126.
NallsMAPankratzNLillCMDoCBHernandezDGSaadM, and others. 2014. Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson’s disease. Nat Genet46(9):989–93.
127.
NimmerjahnAKirchhoffFHelmchenF.2005. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science308(5726):1314–8.
128.
NumataTArayaJFujiiSHaraHTakasakaNKojimaJ, and others. 2011. Insulin-dependent phosphatidylinositol 3-kinase/AKT and ERK signaling pathways inhibit TLR3-mediated human bronchial epithelial cell apoptosis. J Immunol Baltim Md1950187(1):510–9.
129.
OlahMMenonVHabibNTagaMFMaYYungCJ, and others. 2020. Single cell RNA sequencing of human microglia uncovers a subset associated with Alzheimer’s disease. Nat Commun11(1):6129.
130.
OlahMPatrickEVillaniACXuJWhiteCCRyanKJ, and others. 2018. A transcriptomic atlas of aged human microglia. Nat Commun9(1):539.
131.
OrrSJMorganNMElliottJBurrowsJFScottCJMcVicarDW, and others. 2007. CD33 responses are blocked by SOCS3 through accelerated proteasomal-mediated turnover. Blood109(3):1061–8.
132.
ParkYHHodgesASimmonsALovestoneSWeinerMWKimS, and others. 2020. Association of blood-based transcriptional risk scores with biomarkers for Alzheimer disease. Neurol Genet6(6):e517.
PawelecGAkbarACarusoCSolanaRGrubeck-LoebensteinBWikbyA.2005. Human immunosenescence: is it infectious?Immunol Rev205:257–68.
135.
PengQMalhotraSTorchiaJAKerrWGCoggeshallKMHumphreyMB. 2010. TREM2- and DAP12-dependent activation of PI3K requires DAP10 and is inhibited by SHIP1. Sci Signal3(122):ra38.
136.
Pérez-OlivaABMartínez-EsparzaMVicente-FernándezJJMiguelRCSGarcía-PeñarrubiaPHernández-CasellesT.2011. Epitope mapping, expression and post-translational modifications of two isoforms of CD33 (CD33M and CD33M) on lymphoid and myeloid human cells. Glycobiology21(6):757–70.
137.
PiccioLDemingYDel-ÁguilaJLGhezziLHoltzmanDMFaganAM, and others. 2016. Cerebrospinal fluid soluble TREM2 is higher in Alzheimer disease and associated with mutation status. Acta Neuropathol131(6):925–33.
138.
PrietoPCuencaJTravésPGFernández-VelascoMMartín-SanzPBoscáL.2010. Lipoxin A4 impairment of apoptotic signaling in macrophages: implication of the PI3K/AKT and the ERK/NRF-2 defense pathways. Cell Death Differ17(7):1179–88.
139.
RajTRyanKJReplogleJMChibnikLBRosenkrantzLTangA, and others. 2014. CD33: increased inclusion of exon 2 implicates the IG V-set domain in Alzheimer’s disease susceptibility. Hum Mol Genet23(10):2729–36.
140.
RakicSHungYMASmithMSoDTaylerHMVarneyW, and others. 2018. Systemic infection modifies the neuroinflammatory response in late stage Alzheimer’s disease. Acta Neuropathol Commun6(1):88.
141.
RathoreNRamaniSRPantuaHPayandehJBhangaleTWusterA, and others. 2018. Paired immunoglobulin-like type 2 receptor alpha G78R variant alters ligand binding and confers protection to Alzheimer’s disease. PLoS Genet14(11):e1007427.
ReadheadBHaure-MirandeJVFunkCCRichardsMAShannonPHaroutunianV, and others. 2018. Multiscale analysis of independent Alzheimer’s cohorts finds disruption of molecular, genetic, and clinical networks by human herpesvirus. Neuron99(1):64–82.e67.
144.
RehliMPoltorakASchwarzfischerLKrauseSWAndreesenRBeutlerB.2000. PU.1 and interferon consensus sequence-binding protein regulate the myeloid expression of the human toll-like receptor 4 gene. J Biol Chem275(13):9773–81.
145.
ReplogleJMChanGWhiteCCRajTWinnPAEvansDA, and others. 2015. A TREM 1 variant alters the accumulation of Alzheimer-related amyloid pathology. Ann Neurol77(3):469–77.
146.
RéuPKhosraviABernardSMoldJESalehpourMAlkassK, and others. 2017. The lifespan and turnover of microglia in the human brain. Cell Rep20(4):779–84.
147.
RidgePGHoytKBBoehmeKMukherjeeSCranePKHainesJL, and others. 2016. Assessment of the genetic variance of late-onset Alzheimer’s disease. Neurobiol Aging41:200.e213–200.e220.
148.
RogersJLuber-NarodJStyrenSDCivinWH. 1988. Expression of immune system-associated antigens by cells of the human central nervous system: relationship to the pathology of Alzheimer’s disease. Neurobiol Aging9(4):339–49.
149.
Root-BernsteinRFairweatherD.2014. Complexities in the relationship between infection and autoimmunity. Curr Allergy Asthma Rep14(1):407.
150.
RustenhovenJSmithAMSmythLCJanssonDScotterELSwansonMEV, and others. 2018. PU.1 regulates Alzheimer’s disease-associated genes in primary human microglia. Mol Neurodegener13(1):44.
151.
SadeghiKWisgrillLWesselyIDiesnerSCSchüllerSDürrC, and others. 2016a. GM-CSF down-regulates TLR expression via the transcription factor PU.1 in human monocytes. PLoS One11(10):e0162667.
152.
SankowskiRBöttcherCMasudaTGeirsdottirLSagar, SindramE, and others. 2019. Mapping microglia states in the human brain through the integration of high-dimensional techniques. Nat Neurosci22(12):2098–110.
153.
SatohTAriiJSuenagaTWangJKogureAUehoriJ, and others. 2008. Pilralpha is a herpes simplex virus-1 entry coreceptor that associates with glycoprotein B. Cell132(6):935–44.
154.
SayedFATelpoukhovskaiaMKodamaLLiYZhouYLeD, and others. 2018. Differential effects of partial and complete loss of TREM2 on microglial injury response and tauopathy. Proc Natl Acad Sci U S A115(40):10172–7.
155.
SchaferDPLehrmanEKKautzmanAGKoyamaRMardinlyARYamasakiR, and others. 2012. Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron74(4):691–705.
156.
SchlepckowKMonroeKMKleinbergerGCantuti-CastelvetriLParhizkarSXiaD, and others. 2020. Enhancing protective microglial activities with a dual function TREM2 antibody to the stalk region. EMBO Mol Med12(4):e11227.
SchulzCGomez PerdigueroEChorroLSzabo-RogersHCagnardNKierdorfK, and others. 2012. A lineage of myeloid cells independent of MYB and hematopoietic stem cells. Science336(6077):86–90.
159.
SchwarzFSpringerSAAltheideTKVarkiNMGagneuxPVarkiA.2016. Human-specific derived alleles of CD33 and other genes protect against postreproductive cognitive decline. Proc Natl Acad Sci U S A113(1):74–9.
160.
SeshadriSFitzpatrickALIkramMADeStefanoALGudnasonVBoadaM, and others. 2010. Genome-wide analysis of genetic loci associated with Alzheimer disease. JAMA303(18):1832–40.
161.
SharifOKnappS.2008. From expression to signaling: roles of TREM-1 and TREM-2 in innate immunity and bacterial infection. Immunobiology213(9–10):701–13.
162.
SieberMWJaenischNBrehmMGuentherMLinnartz-GerlachBNeumannH, and others. 2013. Attenuated inflammatory response in triggering receptor expressed on myeloid cells 2 (TREM2) knock-out mice following stroke. PLoS One8(1):e52982.
163.
SimsRvan der LeeSJNajACBellenguezCBadarinarayanNJakobsdottirJ, and others. 2017. Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer’s disease. Nat Genet49(9):1373–84.
164.
SosciaSJKirbyJEWashicoskyKJTuckerSMIngelssonMHymanB, and others. 2010. The Alzheimer’s disease-associated amyloid beta-protein is an antimicrobial peptide. PLoS One5(3):e9505.
165.
SperlingRAAisenPSBeckettLABennettDACraftSFaganAM, and others. 2011. Toward defining the preclinical stages of Alzheimer’s disease: recommendations from the National Institute on Aging–Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement7(3):280–92.
166.
SquarzoniPOllerGHoeffelGPont-LezicaLRostaingPLowD, and others. 2014. Microglia modulate wiring of the embryonic forebrain. Cell Rep8(5):1271–9.
167.
StackGStaceyMAHumphreysIR. 2012. Herpesvirus exploitation of host immune inhibitory pathways. Viruses4(8):1182–201.
168.
SteeleNZCarrJSBonhamLWGeierEGDamotteVMillerZA, and others. 2017. Fine-mapping of the human leukocyte antigen locus as a risk factor for Alzheimer disease: a case-control study. PLoS Med14(3):e1002272.
StreitWJ. 2006. Microglial senescence: does the brain’s immune system have an expiration date?Trends Neurosci29(9):506–10.
171.
StreitWJSammonsNWKuhnsAJSparksDL. 2004. Dystrophic microglia in the aging human brain. Glia45(2):208–12.
172.
SudomATalrejaSDanaoJBraggEKegelRMinX, and others. 2018. Molecular basis for the loss-of-function effects of the Alzheimer’s disease-associated R47H variant of the immune receptor TREM2. J Biol Chem293(32):12634–46.
173.
TakahashiKRochfordCDPNeumannH.2005. Clearance of apoptotic neurons without inflammation by microglial triggering receptor expressed on myeloid cells-2. J Exp Med201(4):647–57.
174.
TakaloMWittrahmRWefersBParhizkarSJokivarsiKKuulasmaaT, and others. 2020. The Alzheimer’s disease-associated protective PLCΓ2-P522R variant promotes immune functions. Mol Neurodegener15(1):52.
175.
TaylorVCBuckleyCDDouglasMCodyAJSimmonsDLFreemanSD. 1999. The myeloid-specific sialic acid-binding receptor, CD33, associates with the protein-tyrosine phosphatases, SHP-1 and SHP-2. J Biol Chem274(17):11505–12.
176.
TsaiAPLinPBCDongCMoutinhoMCasaliBTLiuY, and others. 2021. INPP5D expression is associated with risk for Alzheimer’s disease and induced by plaque-associated microglia. Neurobiol Dis153:105303.
van der LeeSJConwayOJJansenICarrasquilloMMKleineidamLvan den AkkerE, and others. 2019. A nonsynonymous mutation in PLCG2 reduces the risk of Alzheimer’s disease, dementia with Lewy bodies and frontotemporal dementia, and increases the likelihood of longevity. Acta Neuropathol138(2):237–50.
179.
WalkerDGTangTMLueLF. 2017. Studies on colony stimulating factor receptor-1 and ligands colony stimulating factor-1 and interleukin-34 in Alzheimer’s disease brains and human microglia. Front Aging Neurosci9:244.
180.
WalkerDGWhetzelAMSerranoGSueLIBeachTGLueLF. 2015. Association of CD33 polymorphism RS3865444 with Alzheimer’s disease pathology and CD33 expression in human cerebral cortex. Neurobiol Aging36(2):571–82.
181.
WalterRBHäusermannPRadenBWTeckchandaniAMKamikuraDMBernsteinID, and others. 2008. Phosphorylated ITIMs enable ubiquitylation of an inhibitory cell surface receptor. Traffic9(2):267–79.
182.
WangSMustafaMYuedeCMSalazarSVKongPLongH, and others. 2020. Anti-human TREM2 induces microglia proliferation and reduces pathology in an Alzheimer’s disease model. J Exp Med217(9):e20200785.
183.
WangYCellaMMallinsonKUlrichJDYoungKLRobinetteML, and others. 2015. TREM2 lipid sensing sustains the microglial response in an Alzheimer’s disease model. Cell160(6):1061–71.
184.
WangYSzretterKJVermiWGilfillanSRossiniCCellaM, and others. 2012. IL-34 is a tissue-restricted ligand of CSF1R required for the development of Langerhans cells and microglia. Nat Immunol13(8):753–60.
185.
WangYUllandTKUlrichJDSongWTzaferisJAHoleJT, and others. 2016. TREM2-mediated early microglial response limits diffusion and toxicity of amyloid plaques. J Exp Med213(5):667–75.
186.
WeiSNandiSChituVYeungYGYuWHuangM, and others. 2010. Functional overlap but differential expression of CSF-1 and IL-34 in their CSF-1 receptor-mediated regulation of myeloid cells. J Leukoc Biol88(3):495–505.
187.
WendelnACDegenhardtKKauraniLGertigMUlasTJainG, and others. 2018. Innate immune memory in the brain shapes neurological disease hallmarks. Nature556(7701):332–8.
188.
WhiteMRKandelRTripathiSCondonDQiLTaubenbergerJ, and others. 2014. Alzheimer’s associated β-amyloid protein inhibits influenza a virus and modulates viral interactions with phagocytes. PLoS One9(7):e101364.
189.
WildsmithKRHolleyMSavageJCSkerrettRLandrethGE. 2013. Evidence for impaired amyloid β clearance in Alzheimer’s disease. Alzheimers Res Ther5(4):33.
190.
WissemannWTHill-BurnsEMZabetianCPFactorSAPatsopoulosNHoglundB, and others. 2013. Association of Parkinson disease with structural and regulatory variants in the HLA region. Am J Hum Genet93(5):984–93.
191.
WlodarskiPZhangQLiuXKasprzyckaMMarzecMWasikMA. 2007. PU.1 activates transcription of SHP-1 gene in hematopoietic cells. J Biol Chem282(9):6316–23.
192.
YaoHCoppolaKSchweigJECrawfordFMullanMParisD.2019. Distinct signaling pathways regulate TREM2 phagocytic and NFκB antagonistic activities. Front Cell Neurosci13:457.
193.
YoonSSJoSA. 2012. Mechanisms of amyloid-β peptide clearance: potential therapeutic targets for Alzheimer’s disease. Biomol Ther (Seoul)20(3):245–55.
194.
YuanPCondelloCKeeneCDWangYBirdTDPaulSM, and others. 2016. TREM2 haplodeficiency in mice and humans impairs the microglia barrier function leading to decreased amyloid compaction and severe axonal dystrophy. Neuron90(4):724–39.
195.
YuanZSyedMAPanchalDJooMColonnaMBrantlyM, and others. 2014. Triggering receptor expressed on myeloid cells 1 (TREM-1)-mediated BCL-2 induction prolongs macrophage survival. J Biol Chem289(21):15118–29.
196.
ZaghiJGoldensonBInayathullahMLossinskyASMasoumiAAvagyanH, and others. 2009. Alzheimer disease macrophages shuttle amyloid-beta from neurons to vessels, contributing to amyloid angiopathy. Acta Neuropathol117(2):111–24.
197.
ZdimerovaHMurerAEngelmannCRaykovaADengYGujerC, and others. 2021. Attenuated immune control of Epstein-Barr virus in humanized mice is associated with the multiple sclerosis risk factor HLA-DR15. Eur J Immunol51(1):64–75.
198.
ZengHOrnatowskaMJooMSSadikotRT. 2007. TREM-1 expression in macrophages is regulated at transcriptional level by NF-κB and PU.1. Eur J Immunol37(8):2300–8.
199.
ZhangBGaiteriCBodeaLGWangZMcElweeJPodtelezhnikovAA, and others. 2013. Integrated systems approach identifies genetic nodes and networks in late-onset Alzheimer’s disease. Cell153(3):707–20.
200.
ZhouQLeeGSBradyJDattaSKatanMSheikhA, and others. 2012. A hypermorphic missense mutation in PLCG2, encoding phospholipase Cγ2, causes a dominantly inherited autoinflammatory disease with immunodeficiency. Am J Hum Genet91(4):713–20.
201.
ZhuLJonesCZhangG.2018. The role of phospholipase c signaling in macrophage-mediated inflammatory response. J Immunol Res2018:5201759.
