1932

Abstract

Advances in human genetics have implicated a growing number of genes in neurodegenerative diseases, providing insight into pathological processes. For Alzheimer disease in particular, genome-wide association studies and gene expression studies have emphasized the pathogenic contributions from microglial cells and motivated studies of microglial function/dysfunction. Here, we summarize recent genetic evidence for microglial involvement in neurodegenerative disease with a focus on Alzheimer disease, for which the evidence is most compelling. To provide context for these genetic discoveries, we discuss how microglia influence brain development and homeostasis, how microglial characteristics change in disease, and which microglial activities likely influence the course of neurodegeneration. In all, we aim to synthesize varied aspects of microglial biology and highlight microglia as possible targets for therapeutic interventions in neurodegenerative disease.

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2019-12-03
2024-06-23
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Literature Cited

  1. 1. 
    Anderson SR, Zhang J, Steele MR, Romero CO, Kautzman AG et al. 2019. Complement targets newborn retinal ganglion cells for phagocytic elimination by microglia. J. Neurosci. 39:2025–40
    [Google Scholar]
  2. 2. 
    Arandjelovic S, Ravichandran KS. 2015. Phagocytosis of apoptotic cells in homeostasis. Nat. Immunol. 16:907–17
    [Google Scholar]
  3. 3. 
    Arnold TD, Lizama CO, Cautivo KM, Santander N, Lin L et al. 2019. Impaired αVβ8 and TGFβ signaling lead to microglial dysmaturation and neuromotor dysfunction. J. Exp. Med. 216:900–15
    [Google Scholar]
  4. 4. 
    Asai H, Ikezu S, Tsunoda S, Medalla M, Luebke J et al. 2015. Depletion of microglia and inhibition of exosome synthesis halt tau propagation. Nat. Neurosci. 18:1584–93
    [Google Scholar]
  5. 5. 
    Ayata P, Badimon A, Strasburger HJ, Duff MK, Montgomery SE et al. 2018. Epigenetic regulation of brain region-specific microglia clearance activity. Nat. Neurosci. 21:1049–60
    [Google Scholar]
  6. 6. 
    Bennett FC, Bennett ML, Yaqoob F, Mulinyawe SB, Grant GA et al. 2018. A combination of ontogeny and CNS environment establishes microglial identity. Neuron 98:1170–83.e8Transplantation studies illustrating the importance of both ontogeny and environment in microglial specialization.
    [Google Scholar]
  7. 7. 
    Blank T, Prinz M. 2017. Type I interferon pathway in CNS homeostasis and neurological disorders. Glia 65:1397–406
    [Google Scholar]
  8. 8. 
    Bohlen CJ, Bennett FC, Tucker AF, Collins HY, Mulinyawe SB, Barres BA 2017. Diverse requirements for microglial survival, specification, and function revealed by defined-medium cultures. Neuron 94:759–73.e8
    [Google Scholar]
  9. 9. 
    Bradshaw EM, Chibnik LB, Keenan BT, Ottoboni L, Raj T et al. 2013. CD33 Alzheimer's disease locus: altered monocyte function and amyloid biology. Nat. Neurosci. 16:848–50
    [Google Scholar]
  10. 10. 
    Britschgi M, Takeda-Uchimura Y, Rockenstein E, Johns H, Masliah E, Wyss-Coray T 2012. Deficiency of terminal complement pathway inhibitor promotes neuronal tau pathology and degeneration in mice. J. Neuroinflamm. 9:220
    [Google Scholar]
  11. 11. 
    Bruttger J, Karram K, Wortge S, Regen T, Marini F et al. 2015. Genetic cell ablation reveals clusters of local self-renewing microglia in the mammalian central nervous system. Immunity 43:92–106
    [Google Scholar]
  12. 12. 
    Butovsky O, Jedrychowski MP, Moore CS, Cialic R, Lanser AJ et al. 2014. Identification of a unique TGF-β-dependent molecular and functional signature in microglia. Nat. Neurosci. 17:131–43
    [Google Scholar]
  13. 13. 
    Butovsky O, Talpalar AE, Ben-Yaakov K, Schwartz M 2005. Activation of microglia by aggregated β-amyloid or lipopolysaccharide impairs MHC-II expression and renders them cytotoxic whereas IFN-gamma and IL-4 render them protective. Mol. Cell Neurosci. 29:381–93
    [Google Scholar]
  14. 14. 
    Buttgereit A, Lelios I, Yu XY, Vrohlings M, Krakoski NR et al. 2016. Sall1 is a transcriptional regulator defining microglia identity and function. Nat. Immunol. 17:1397–406Illustrates the importance of Sall1 and TGFBR2 in maintaining microglial specialization and homeostatic functions.
    [Google Scholar]
  15. 15. 
    Cannon JP, O'Driscoll M, Litman GW 2012. Specific lipid recognition is a general feature of CD300 and TREM molecules. Immunogenetics 64:39–47
    [Google Scholar]
  16. 16. 
    Cantoni C, Bollman B, Licastro D, Xie M, Mikesell R et al. 2015. TREM2 regulates microglial cell activation in response to demyelination in vivo. Acta Neuropathol 129:429–47
    [Google Scholar]
  17. 17. 
    Cantuti-Castelvetri L, Fitzner D, Bosch-Queralt M, Weil MT, Su M et al. 2018. Defective cholesterol clearance limits remyelination in the aged central nervous system. Science 359:684–88Illustrates the functional consequences of increased myelin burden in aged microglia.
    [Google Scholar]
  18. 18. 
    Chang D, Nalls MA, Hallgrímsdóttir IB, Hunkapiller J, van der Brug M et al. 2017. A meta-analysis of genome-wide association studies identifies 17 new Parkinson's disease risk loci. Nat. Genet. 49:1511–16
    [Google Scholar]
  19. 19. 
    Checchin D, Sennlaub F, Levavasseur E, Leduc M, Chemtob S 2006. Potential role of microglia in retinal blood vessel formation. Investig. Ophthalmol. Vis. Sci. 47:3595–602
    [Google Scholar]
  20. 20. 
    Chen P, Zhao W, Guo Y, Xu J, Yin M 2016. CX3CL1/CX3CR1 in Alzheimer's disease: a target for neuroprotection. Biomed. Res. Int. 2016:8090918
    [Google Scholar]
  21. 21. 
    Cheng-Hathaway PJ, Reed-Geaghan EG, Jay TR, Casali BT, Bemiller SM et al. 2018. The Trem2 R47H variant confers loss-of-function-like phenotypes in Alzheimer's disease. Mol. Neurodegener. 13:29
    [Google Scholar]
  22. 22. 
    Chiu IM, Morimoto ET, Goodarzi H, Liao JT, O'Keeffe S et al. 2013. A neurodegeneration-specific gene-expression signature of acutely isolated microglia from an amyotrophic lateral sclerosis mouse model. Cell Rep 4:385–401An early analysis of microglial transcriptional changes in an ALS model, contrasted with LPS stimulation.
    [Google Scholar]
  23. 23. 
    Chung WS, Clarke LE, Wang GX, Stafford BK, Sher A et al. 2013. Astrocytes mediate synapse elimination through MEGF10 and MERTK pathways. Nature 504:394–400
    [Google Scholar]
  24. 24. 
    Cochain C, Vafadarnejad E, Arampatzi P, Pelisek J, Winkels H et al. 2018. Single-cell RNA-Seq reveals the transcriptional landscape and heterogeneity of aortic macrophages in murine atherosclerosis. Circ. Res. 122:1661–74
    [Google Scholar]
  25. 25. 
    Condello C, Yuan P, Schain A, Grutzendler J 2015. Microglia constitute a barrier that prevents neurotoxic protofibrillar Aβ42 hotspots around plaques. Nat. Commun. 6:6176
    [Google Scholar]
  26. 26. 
    Corbett BA, Kantor AB, Schulman H, Walker WL, Lit L et al. 2007. A proteomic study of serum from children with autism showing differential expression of apolipoproteins and complement proteins. Mol. Psychiatry 12:292–306
    [Google Scholar]
  27. 27. 
    Cunningham CL, Martínez-Cerdeño V, Noctor SC 2013. Microglia regulate the number of neural precursor cells in the developing cerebral cortex. J. Neurosci. 33:4216–33
    [Google Scholar]
  28. 28. 
    De Jager PL, Ma Y, McCabe C, Xu J, Vardarajan BN et al. 2018. A multi-omic atlas of the human frontal cortex for aging and Alzheimer's disease research. Sci. Data 5:180142
    [Google Scholar]
  29. 29. 
    Dejanovic B, Huntley MA, De Mazière A, Meilandt WJ, Wu T et al. 2018. Changes in the synaptic proteome in tauopathy and rescue of Tau-induced synapse loss by C1q antibodies. Neuron 100:1322–36.e7
    [Google Scholar]
  30. 30. 
    El Khoury J, Toft M, Hickman SE, Means TK, Terada K et al. 2007. Ccr2 deficiency impairs microglial accumulation and accelerates progression of Alzheimer-like disease. Nat. Med. 13:432–38
    [Google Scholar]
  31. 31. 
    Elmore MRP, Hohsfield LA, Kramar EA, Soreq L, Lee RJ et al. 2018. Replacement of microglia in the aged brain reverses cognitive, synaptic, and neuronal deficits in mice. Aging Cell 17:e12832
    [Google Scholar]
  32. 32. 
    Erny D, Hrabě de Angelis AL, Jaitin D, Wieghofer P, Staszewski O et al. 2015. Host microbiota constantly control maturation and function of microglia in the CNS. Nat. Neurosci. 18:965–77
    [Google Scholar]
  33. 33. 
    Erturk A, Wang Y, Sheng M 2014. Local pruning of dendrites and spines by caspase-3-dependent and proteasome-limited mechanisms. J. Neurosci. 34:1672–88
    [Google Scholar]
  34. 34. 
    Fonseca MI, Ager RR, Chu SH, Yazan O, Sanderson SD et al. 2009. Treatment with a C5aR antagonist decreases pathology and enhances behavioral performance in murine models of Alzheimer's disease. J. Immunol. 183:1375–83
    [Google Scholar]
  35. 35. 
    Fonseca MI, Zhou J, Botto M, Tenner AJ 2004. Absence of C1q leads to less neuropathology in transgenic mouse models of Alzheimer's disease. J. Neurosci. 24:6457–65
    [Google Scholar]
  36. 36. 
    Fourgeaud L, Traves PG, Tufail Y, Leal-Bailey H, Lew ED et al. 2016. TAM receptors regulate multiple features of microglial physiology. Nature 532:240–44
    [Google Scholar]
  37. 37. 
    Frenkel D, Wilkinson K, Zhao L, Hickman SE, Means TK et al. 2013. Scara1 deficiency impairs clearance of soluble amyloid-β by mononuclear phagocytes and accelerates Alzheimer's-like disease progression. Nat. Commun. 4:2030
    [Google Scholar]
  38. 38. 
    Friedman BA, Srinivasan K, Ayalon G, Meilandt WJ, Lin H et al. 2018. Diverse brain myeloid expression profiles reveal distinct microglial activation states and aspects of Alzheimer's disease not evident in mouse models. Cell Rep 22:832–47 https://doi.org/10.1016/j.celrep.2017.12.066 Defines microglial gene expression modules across multiple models of neural damage and/or inflammation.
    [Crossref] [Google Scholar]
  39. 39. 
    Galatro TF, Holtman IR, Lerario AM, Vainchtein ID, Brouwer N et al. 2017. Transcriptomic analysis of purified human cortical microglia reveals age-associated changes. Nat. Neurosci. 20:1162–71
    [Google Scholar]
  40. 40. 
    Gautier EL, Yvan-Charvet L. 2014. Understanding macrophage diversity at the ontogenic and transcriptomic levels. Immunol. Rev. 262:85–95
    [Google Scholar]
  41. 41. 
    Gosselin D, Link VM, Romanoski CE, Fonseca GJ, Eichenfield DZ et al. 2014. Environment drives selection and function of enhancers controlling tissue-specific macrophage identities. Cell 159:1327–40
    [Google Scholar]
  42. 42. 
    Gosselin D, Skola D, Coufal NG, Holtman IR, Schlachetzki JCM et al. 2017. An environment-dependent transcriptional network specifies human microglia identity. Science 356:eaal3222
    [Google Scholar]
  43. 43. 
    Grabert K, Michoel T, Karavolos MH, Clohisey S, Baillie JK et al. 2016. Microglial brain region-dependent diversity and selective regional sensitivities to aging. Nat. Neurosci. 19:504–16
    [Google Scholar]
  44. 44. 
    Griciuc A, Serrano-Pozo A, Parrado AR, Lesinski AN, Asselin CN et al. 2013. Alzheimer's disease risk gene CD33 inhibits microglial uptake of amyloid beta. Neuron 78:631–43
    [Google Scholar]
  45. 45. 
    Guan Z, Kuhn JA, Wang X, Colquitt B, Solorzano C et al. 2016. Injured sensory neuron-derived CSF1 induces microglial proliferation and DAP12-dependent pain. Nat. Neurosci. 19:94–101
    [Google Scholar]
  46. 46. 
    Habib N, Avraham-Davidi I, Basu A, Burks T, Shekhar K et al. 2017. Massively parallel single-nucleus RNA-seq with DroNc-seq. Nat. Methods 14:955–58
    [Google Scholar]
  47. 47. 
    Hagemeyer N, Hanft KM, Akriditou MA, Unger N, Park ES et al. 2017. Microglia contribute to normal myelinogenesis and to oligodendrocyte progenitor maintenance during adulthood. Acta Neuropathol 134:441–58
    [Google Scholar]
  48. 48. 
    Hammond TR, Dufort C, Dissing-Olesen L, Giera S, Young A et al. 2019. Single-cell RNA sequencing of microglia throughout the mouse lifespan and in the injured brain reveals complex cell-state changes. Immunity 50:253–71.e6
    [Google Scholar]
  49. 49. 
    Haney MS, Bohlen CJ, Morgens DW, Ousey JA, Barkal AA et al. 2018. Identification of phagocytosis regulators using magnetic genome-wide CRISPR screens. Nat. Genet. 50:1716–27
    [Google Scholar]
  50. 50. 
    Hansen DV, Hanson JE, Sheng M 2018. Microglia in Alzheimer's disease. J. Cell Biol. 217:459–72
    [Google Scholar]
  51. 51. 
    Hart AD, Wyttenbach A, Perry VH, Teeling JL 2012. Age related changes in microglial phenotype vary between CNS regions: grey versus white matter differences. Brain Behav. Immun. 26:754–65
    [Google Scholar]
  52. 52. 
    Hefendehl JK, Neher JJ, Suhs RB, Kohsaka S, Skodras A, Jucker M 2014. Homeostatic and injury-induced microglia behavior in the aging brain. Aging Cell 13:60–69
    [Google Scholar]
  53. 53. 
    Hellwig S, Heinrich A, Biber K 2013. The brain's best friend: microglial neurotoxicity revisited. Front. Cell Neurosci. 7:71
    [Google Scholar]
  54. 54. 
    Heneka MT, Kummer MP, Stutz A, Delekate A, Schwartz S et al. 2013. NLRP3 is activated in Alzheimer's disease and contributes to pathology in APP/PS1 mice. Nature 493:674–78
    [Google Scholar]
  55. 55. 
    Hickman SE, Kingery ND, Ohsumi TK, Borowsky ML, Wang LC et al. 2013. The microglial sensome revealed by direct RNA sequencing. Nat. Neurosci. 16:1896–905
    [Google Scholar]
  56. 56. 
    Hill RA, Li AM, Grutzendler J 2018. Lifelong cortical myelin plasticity and age-related degeneration in the live mammalian brain. Nat. Neurosci. 21:683–95
    [Google Scholar]
  57. 57. 
    Holtman IR, Raj DD, Miller JA, Schaafsma W, Yin Z et al. 2015. Induction of a common microglia gene expression signature by aging and neurodegenerative conditions: a co-expression meta-analysis. Acta Neuropathol. Commun. 3:31
    [Google Scholar]
  58. 58. 
    Holtzman DM, Herz J, Bu G 2012. Apolipoprotein E and apolipoprotein E receptors: normal biology and roles in Alzheimer disease. Cold Spring Harb. Perspect. Med. 2:a006312
    [Google Scholar]
  59. 59. 
    Hong S, Beja-Glasser VF, Nfonoyim BM, Frouin A, Li S et al. 2016. Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science 352:712–16Illustrates complement-mediated synapse elimination in AD.
    [Google Scholar]
  60. 60. 
    Hopp SC, Lin Y, Oakley D, Roe AD, DeVos SL et al. 2018. The role of microglia in processing and spreading of bioactive tau seeds in Alzheimer's disease. J. Neuroinflamm. 15:269
    [Google Scholar]
  61. 61. 
    Hopperton KE, Mohammad D, Trepanier MO, Giuliano V, Bazinet RP 2018. Markers of microglia in post-mortem brain samples from patients with Alzheimer's disease: a systematic review. Mol. Psychiatry 23:177–98
    [Google Scholar]
  62. 62. 
    Hoshiko M, Arnoux I, Avignone E, Yamamoto N, Audinat E 2012. Deficiency of the microglial receptor CX3CR1 impairs postnatal functional development of thalamocortical synapses in the barrel cortex. J. Neurosci. 32:15106–11
    [Google Scholar]
  63. 63. 
    Huang KL, Marcora E, Pimenova AA, Di Narzo AF, Kapoor M et al. 2017. A common haplotype lowers PU.1 expression in myeloid cells and delays onset of Alzheimer's disease. Nat. Neurosci. 20:1052–61
    [Google Scholar]
  64. 64. 
    Hüttenrauch M, Ogorek I, Klafki H, Otto M, Stadelmann C et al. 2018. Glycoprotein NMB: a novel Alzheimer's disease associated marker expressed in a subset of activated microglia. Acta Neuropathol. Commun. 6:108
    [Google Scholar]
  65. 65. 
    Jakobsdottir J, van der Lee SJ, Bis JC, Chouraki V, Li-Kroeger D et al. 2016. Rare functional variant in TM2D3 is associated with late-onset Alzheimer's disease. PLOS Genet 12:e1006327
    [Google Scholar]
  66. 66. 
    Jankowsky JL, Zheng H. 2017. Practical considerations for choosing a mouse model of Alzheimer's disease. Mol. Neurodegener. 12:89
    [Google Scholar]
  67. 67. 
    Jansen IE, Savage JE, Watanabe K, Bryois J, Williams DM et al. 2019. Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer's disease risk. Nat. Genet. 51:404–13
    [Google Scholar]
  68. 68. 
    Jobling AI, Waugh M, Vessey KA, Phipps JA, Trogrlic L et al. 2018. The role of the microglial Cx3cr1 pathway in the postnatal maturation of retinal photoreceptors. J. Neurosci. 38:4708–23
    [Google Scholar]
  69. 69. 
    Joshi P, Turola E, Ruiz A, Bergami A, Libera DD et al. 2014. Microglia convert aggregated amyloid-β into neurotoxic forms through the shedding of microvesicles. Cell Death Differ 21:582–93
    [Google Scholar]
  70. 70. 
    Keren-Shaul H, Spinrad A, Weiner A, Matcovitch-Natan O, Dvir-Szternfeld R et al. 2017. A unique microglia type associated with restricting development of Alzheimer's disease. Cell 169:1276–90.e17Single-cell characterization of microglial transcriptional responses in a mouse model of amyloidosis.
    [Google Scholar]
  71. 71. 
    Kim K, Shim D, Lee JS, Zaitsev K, Williams JW et al. 2018. Transcriptome analysis reveals nonfoamy rather than foamy plaque macrophages are proinflammatory in atherosclerotic murine models. Circ. Res. 123:1127–42
    [Google Scholar]
  72. 72. 
    Klünemann HH, Ridha BH, Magy L, Wherrett JR, Hemelsoet DM et al. 2005. The genetic causes of basal ganglia calcification, dementia, and bone cysts: DAP12 and TREM2. Neurology 64:1502–7
    [Google Scholar]
  73. 73. 
    Kohyama M, Ise W, Edelson BT, Wilker PR, Hildner K et al. 2009. Role for Spi-C in the development of red pulp macrophages and splenic iron homeostasis. Nature 457:318–21
    [Google Scholar]
  74. 74. 
    Kranich J, Krautler NJ, Falsig J, Ballmer B, Li S et al. 2010. Engulfment of cerebral apoptotic bodies controls the course of prion disease in a mouse strain–dependent manner. J. Exp. Med. 207:2271–81
    [Google Scholar]
  75. 75. 
    Krasemann S, Madore C, Cialic R, Baufeld C, Calcagno N et al. 2017. The TREM2-APOE pathway drives the transcriptional phenotype of dysfunctional microglia in neurodegenerative diseases. Immunity 47:566–81.e9
    [Google Scholar]
  76. 76. 
    Kunkle BW, Grenier-Boley B, Sims R, Bis JC, Damotte V et al. 2019. Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing. Nat. Genet. 51:414–30
    [Google Scholar]
  77. 77. 
    Ladu MJ, Reardon C, Van Eldik L, Fagan AM, Bu G et al. 2000. Lipoproteins in the central nervous system. Ann. N.Y. Acad. Sci. 903:167–75
    [Google Scholar]
  78. 78. 
    Lake BB, Chen S, Sos BC, Fan J, Kaeser GE et al. 2018. Integrative single-cell analysis of transcriptional and epigenetic states in the human adult brain. Nat. Biotechnol. 36:70–80Single-nucleus study from human brain analyzing cell-type-specific expression and chromatin patterns at GWAS loci.
    [Google Scholar]
  79. 79. 
    Lambert JC, Ibrahim-Verbaas CA, Harold D, Naj AC, Sims R et al. 2013. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease. Nat. Genet. 45:1452–58
    [Google Scholar]
  80. 80. 
    Landreth GE, Reed-Geaghan EG. 2009. Toll-like receptors in Alzheimer's disease. Curr. Top. Microbiol. Immunol. 336:137–53
    [Google Scholar]
  81. 81. 
    Lavin Y, Winter D, Blecher-Gonen R, David E, Keren-Shaul H et al. 2014. Tissue-resident macrophage enhancer landscapes are shaped by the local microenvironment. Cell 159:1312–26
    [Google Scholar]
  82. 82. 
    Lee CYD, Daggett A, Gu X, Jiang LL, Langfelder P et al. 2018. Elevated TREM2 gene dosage reprograms microglia responsivity and ameliorates pathological phenotypes in Alzheimer's disease models. Neuron 97:1032–48.e5
    [Google Scholar]
  83. 83. 
    Lessard CB, Malnik SL, Zhou Y, Ladd TB, Cruz PE et al. 2018. High-affinity interactions and signal transduction between Aβ oligomers and TREM2. EMBO Mol. Med. 10:e9027
    [Google Scholar]
  84. 84. 
    Leyns CEG, Ulrich JD, Finn MB, Stewart FR, Koscal LJ et al. 2017. TREM2 deficiency attenuates neuroinflammation and protects against neurodegeneration in a mouse model of tauopathy. PNAS 114:11524–29
    [Google Scholar]
  85. 85. 
    Li Q, Barres BA. 2018. Microglia and macrophages in brain homeostasis and disease. Nat. Rev. Immunol. 18:225–42
    [Google Scholar]
  86. 86. 
    Li Q, Cheng Z, Zhou L, Darmanis S, Neff NF et al. 2019. Developmental heterogeneity of microglia and brain myeloid cells revealed by deep single-cell RNA sequencing. Neuron 101:207–23.e10
    [Google Scholar]
  87. 87. 
    Li Y, Du XF, Liu CS, Wen ZL, Du JL 2012. Reciprocal regulation between resting microglial dynamics and neuronal activity in vivo. Dev. Cell 23:1189–202
    [Google Scholar]
  88. 88. 
    Liao F, Hori Y, Hudry E, Bauer AQ, Jiang H et al. 2014. Anti-ApoE antibody given after plaque onset decreases Aβ accumulation and improves brain function in a mouse model of Aβ amyloidosis. J. Neurosci. 34:7281–92
    [Google Scholar]
  89. 89. 
    Liddelow SA, Guttenplan KA, Clarke LE, Bennett FC, Bohlen CJ et al. 2017. Neurotoxic reactive astrocytes are induced by activated microglia. Nature 541:481–87
    [Google Scholar]
  90. 90. 
    Litvinchuk A, Wan YW, Swartzlander DB, Chen F, Cole A et al. 2018. Complement C3aR inactivation attenuates Tau pathology and reverses an immune network deregulated in tauopathy models and Alzheimer's disease. Neuron 100:1337–53.e5
    [Google Scholar]
  91. 91. 
    Liu Z, Condello C, Schain A, Harb R, Grutzendler J 2010. CX3CR1 in microglia regulates brain amyloid deposition through selective protofibrillar amyloid-β phagocytosis. J. Neurosci. 30:17091–101
    [Google Scholar]
  92. 92. 
    Lui H, Zhang J, Makinson SR, Cahill MK, Kelley KW et al. 2016. Progranulin deficiency promotes circuit-specific synaptic pruning by microglia via complement activation. Cell 165:921–35
    [Google Scholar]
  93. 93. 
    Lund H, Pieber M, Harris RA 2017. Lessons learned about neurodegeneration from microglia and monocyte depletion studies. Front. Aging Neurosci. 9:234
    [Google Scholar]
  94. 94. 
    Lund H, Pieber M, Parsa R, Grommisch D, Ewing E et al. 2018. Fatal demyelinating disease is induced by monocyte-derived macrophages in the absence of TGF-β signaling. Nat. Immunol. 19:1–7
    [Google Scholar]
  95. 95. 
    Maier M, Peng Y, Jiang L, Seabrook TJ, Carroll MC, Lemere CA 2008. Complement C3 deficiency leads to accelerated amyloid β plaque deposition and neurodegeneration and modulation of the microglia/macrophage phenotype in amyloid precursor protein transgenic mice. J. Neurosci. 28:6333–41
    [Google Scholar]
  96. 96. 
    Makwana M, Jones LL, Cuthill D, Heuer H, Bohatschek M et al. 2007. Endogenous transforming growth factor β1 suppresses inflammation and promotes survival in adult CNS. J. Neurosci. 27:11201–13
    [Google Scholar]
  97. 97. 
    Marioni RE, Harris SE, Zhang Q, McRae AF, Hagenaars SP et al. 2018. GWAS on family history of Alzheimer's disease. Transl. Psychiatry 8:99
    [Google Scholar]
  98. 98. 
    Masuda T, Sankowski R, Staszewski O, Böttcher C, Amann L et al. 2019. Spatial and temporal heterogeneity of mouse and human microglia at single-cell resolution. Nature 566:388–92
    [Google Scholar]
  99. 99. 
    Matcovitch-Natan O, Winter DR, Giladi A, Vargas Aguilar S, Spinrad A et al. 2016. Microglia development follows a stepwise program to regulate brain homeostasis. Science 353:aad8670
    [Google Scholar]
  100. 100. 
    Mathys H, Adaikkan C, Gao F, Young JZ, Manet E et al. 2017. Temporal tracking of microglia activation in neurodegeneration at single-cell resolution. Cell Rep 21:366–80
    [Google Scholar]
  101. 101. 
    Mazaheri F, Breus O, Durdu S, Haas P, Wittbrodt J et al. 2014. Distinct roles for BAI1 and TIM-4 in the engulfment of dying neurons by microglia. Nat. Commun. 5:4046
    [Google Scholar]
  102. 102. 
    Michaud JP, Richard KL, Rivest S 2011. MyD88-adaptor protein acts as a preventive mechanism for memory deficits in a mouse model of Alzheimer's disease. Mol. Neurodegener. 6:5
    [Google Scholar]
  103. 103. 
    Miyamoto A, Wake H, Ishikawa AW, Eto K, Shibata K et al. 2016. Microglia contact induces synapse formation in developing somatosensory cortex. Nat. Commun. 7:12540
    [Google Scholar]
  104. 104. 
    Mostafavi S, Gaiteri C, Sullivan SE, White CC, Tasaki S et al. 2018. A molecular network of the aging human brain provides insights into the pathology and cognitive decline of Alzheimer's disease. Nat. Neurosci. 21:811–19
    [Google Scholar]
  105. 105. 
    Mrdjen D, Pavlovic A, Hartmann FJ, Schreiner B, Utz SG et al. 2018. High-dimensional single-cell mapping of central nervous system immune cells reveals distinct myeloid subsets in health, aging, and disease. Immunity 48:380–95.e6
    [Google Scholar]
  106. 106. 
    Nandi S, Gokhan S, Dai XM, Wei S, Enikolopov G et al. 2012. The CSF-1 receptor ligands IL-34 and CSF-1 exhibit distinct developmental brain expression patterns and regulate neural progenitor cell maintenance and maturation. Dev. Biol. 367:100–13
    [Google Scholar]
  107. 107. 
    Neher JJ, Emmrich JV, Fricker M, Mander PK, Thery C, Brown GC 2013. Phagocytosis executes delayed neuronal death after focal brain ischemia. PNAS 110:E4098–107
    [Google Scholar]
  108. 108. 
    Nelson PT, Alafuzoff I, Bigio EH, Bouras C, Braak H et al. 2012. Correlation of Alzheimer disease neuropathologic changes with cognitive status: a review of the literature. J. Neuropathol. Exp. Neurol. 71:362–81
    [Google Scholar]
  109. 109. 
    Neniskyte U, Gross CT. 2017. Errant gardeners: glial-cell-dependent synaptic pruning and neurodevelopmental disorders. Nat. Rev. Neurosci. 18:658–70
    [Google Scholar]
  110. 110. 
    Norden DM, Muccigrosso MM, Godbout JP 2015. Microglial priming and enhanced reactivity to secondary insult in aging, and traumatic CNS injury, and neurodegenerative disease. Neuropharmacology 96:29–41
    [Google Scholar]
  111. 111. 
    O'Neil SM, Witcher KG, McKim DB, Godbout JP 2018. Forced turnover of aged microglia induces an intermediate phenotype but does not rebalance CNS environmental cues driving priming to immune challenge. Acta Neuropathol. Commun. 6:129
    [Google Scholar]
  112. 112. 
    Okabe Y, Medzhitov R. 2014. Tissue-specific signals control reversible program of localization and functional polarization of macrophages. Cell 157:832–44
    [Google Scholar]
  113. 113. 
    Paolicelli RC, Bolasco G, Pagani F, Maggi L, Scianni M et al. 2011. Synaptic pruning by microglia is necessary for normal brain development. Science 333:1456–58
    [Google Scholar]
  114. 114. 
    Parhizkar S, Arzberger T, Brendel M, Kleinberger G, Deussing M et al. 2019. Loss of TREM2 function increases amyloid seeding but reduces plaque-associated ApoE. Nat. Neurosci. 22:191–204
    [Google Scholar]
  115. 115. 
    Poliani PL, Wang Y, Fontana E, Robinette ML, Yamanishi Y et al. 2015. TREM2 sustains microglial expansion during aging and response to demyelination. J. Clin. Investig. 125:2161–70
    [Google Scholar]
  116. 116. 
    Qin Y, Garrison BS, Ma W, Wang R, Jiang A et al. 2018. A milieu molecule for TGF-β required for microglia function in the nervous system. Cell 174:156–71.e16
    [Google Scholar]
  117. 117. 
    Rathore N, Ramani SR, Pantua H, Payandeh J, Bhangale T et al. 2018. Paired immunoglobulin-like type 2 receptor alpha G78R variant alters ligand binding and confers protection to Alzheimer's disease. PLOS Genet 14:e1007427
    [Google Scholar]
  118. 118. 
    Reed-Geaghan EG, Reed QW, Cramer PE, Landreth GE 2010. Deletion of CD14 attenuates Alzheimer's disease pathology by influencing the brain's inflammatory milieu. J. Neurosci. 30:15369–73
    [Google Scholar]
  119. 119. 
    Ribeiro Xavier AL, Kress BT, Goldman SA, Lacerda de Menezes JR, Nedergaard M 2015. A distinct population of microglia supports adult neurogenesis in the subventricular zone. J. Neurosci. 35:11848–61
    [Google Scholar]
  120. 120. 
    Richard KL, Filali M, Préfontaine P, Rivest S 2008. Toll-like receptor 2 acts as a natural innate immune receptor to clear amyloid β1–42 and delay the cognitive decline in a mouse model of Alzheimer's disease. J. Neurosci. 28:5784–93
    [Google Scholar]
  121. 121. 
    Rogers J, Cooper NR, Webster S, Schultz J, McGeer PL et al. 1992. Complement activation by beta-amyloid in Alzheimer disease. PNAS 89:10016–20
    [Google Scholar]
  122. 122. 
    Ruckh JM, Zhao JW, Shadrach JL, van Wijngaarden P, Rao TN et al. 2012. Rejuvenation of regeneration in the aging central nervous system. Cell Stem Cell 10:96–103
    [Google Scholar]
  123. 123. 
    Safaiyan S, Kannaiyan N, Snaidero N, Brioschi S, Biber K et al. 2016. Age-related myelin degradation burdens the clearance function of microglia during aging. Nat. Neurosci. 19:995–98
    [Google Scholar]
  124. 124. 
    Schafer DP, Lehrman EK, Kautzman AG, Koyama R, Mardinly AR et al. 2012. Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron 74:691–705
    [Google Scholar]
  125. 125. 
    Sekar A, Bialas AR, de Rivera H, Davis A, Hammond TR et al. 2016. Schizophrenia risk from complex variation of complement component 4. Nature 530:177–83
    [Google Scholar]
  126. 126. 
    Selkoe DJ, Hardy J. 2016. The amyloid hypothesis of Alzheimer's disease at 25 years. EMBO Mol. Med. 8:595–608
    [Google Scholar]
  127. 127. 
    Selmaj K, Raine CS, Farooq M, Norton WT, Brosnan CF 1991. Cytokine cytotoxicity against oligodendrocytes. Apoptosis induced by lymphotoxin. J. Immunol. 147:1522–29
    [Google Scholar]
  128. 128. 
    Shemer A, Grozovski J, Tay TL, Tao J, Volaski A et al. 2018. Engrafted parenchymal brain macrophages differ from microglia in transcriptome, chromatin landscape and response to challenge. Nat. Commun. 9:5206
    [Google Scholar]
  129. 129. 
    Shi Q, Chowdhury S, Ma R, Le KX, Hong S et al. 2017. Complement C3 deficiency protects against neurodegeneration in aged plaque-rich APP/PS1 mice. Sci. Transl. Med. 9:eaaf6295
    [Google Scholar]
  130. 130. 
    Shi Y, Yamada K, Liddelow SA, Smith ST, Zhao L et al. 2017. ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy. Nature 549:523–27
    [Google Scholar]
  131. 131. 
    Sierra A, Gottfried-Blackmore AC, McEwen BS, Bulloch K 2007. Microglia derived from aging mice exhibit an altered inflammatory profile. Glia 55:412–24
    [Google Scholar]
  132. 132. 
    Simons M, Nave KA. 2015. Oligodendrocytes: myelination and axonal support. Cold Spring Harb. Perspect. Biol. 8:a020479
    [Google Scholar]
  133. 133. 
    Sliter DA, Martinez J, Hao L, Chen X, Sun N et al. 2018. Parkin and PINK1 mitigate STING-induced inflammation. Nature 561:258–62
    [Google Scholar]
  134. 134. 
    Song WM, Joshita S, Zhou Y, Ulland TK, Gilfillan S, Colonna M 2018. Humanized TREM2 mice reveal microglia-intrinsic and -extrinsic effects of R47H polymorphism. J. Exp. Med. 215:745–60
    [Google Scholar]
  135. 135. 
    Sosna J, Philipp S, Albay R 3rd, Reyes-Ruiz JM, Baglietto-Vargas D et al. 2018. Early long-term administration of the CSF1R inhibitor PLX3397 ablates microglia and reduces accumulation of intraneuronal amyloid, neuritic plaque deposition and pre-fibrillar oligomers in 5XFAD mouse model of Alzheimer's disease. Mol. Neurodegener. 13:11
    [Google Scholar]
  136. 136. 
    Squarzoni P, Oller G, Hoeffel G, Pont-Lezica L, Rostaing P et al. 2014. Microglia modulate wiring of the embryonic forebrain. Cell Rep 8:1271–79
    [Google Scholar]
  137. 137. 
    Srinivasan K, Friedman BA, Larson JL, Lauffer BE, Goldstein LD et al. 2016. Untangling the brain's neuroinflammatory and neurodegenerative transcriptional responses. Nat. Commun. 7:11295
    [Google Scholar]
  138. 138. 
    Stephan AH, Madison DV, Mateos JM, Fraser DA, Lovelett EA et al. 2013. A dramatic increase of C1q protein in the CNS during normal aging. J. Neurosci. 33:13460–74
    [Google Scholar]
  139. 139. 
    Stevens B, Allen NJ, Vazquez LE, Howell GR, Christopherson KS et al. 2007. The classical complement cascade mediates CNS synapse elimination. Cell 131:1164–78
    [Google Scholar]
  140. 140. 
    Takahashi K, Rochford CD, Neumann H 2005. Clearance of apoptotic neurons without inflammation by microglial triggering receptor expressed on myeloid cells-2. J. Exp. Med. 201:647–57
    [Google Scholar]
  141. 141. 
    Town T, Laouar Y, Pittenger C, Mori T, Szekely CA et al. 2008. Blocking TGF-β-Smad2/3 innate immune signaling mitigates Alzheimer-like pathology. Nat. Med. 14:681–87
    [Google Scholar]
  142. 142. 
    Tremblay ME, Lowery RL, Majewska AK 2010. Microglial interactions with synapses are modulated by visual experience. PLOS Biol 8:e1000527
    [Google Scholar]
  143. 143. 
    Ueno M, Fujita Y, Tanaka T, Nakamura Y, Kikuta J et al. 2013. Layer V cortical neurons require microglial support for survival during postnatal development. Nat. Neurosci. 16:543–51
    [Google Scholar]
  144. 144. 
    Ulland TK, Colonna M. 2018. TREM2 – a key player in microglial biology and Alzheimer disease. Nat. Rev. Neurol. 14:667–75
    [Google Scholar]
  145. 145. 
    Ulrich JD, Ulland TK, Mahan TE, Nyström S, Nilsson KP et al. 2018. ApoE facilitates the microglial response to amyloid plaque pathology. J. Exp. Med. 215:1047–58
    [Google Scholar]
  146. 146. 
    Vasek MJ, Garber C, Dorsey D, Durrant DM, Bollman B et al. 2016. A complement-microglial axis drives synapse loss during virus-induced memory impairment. Nature 534:538–43
    [Google Scholar]
  147. 147. 
    Venegas C, Kumar S, Franklin BS, Dierkes T, Brinkschulte R et al. 2017. Microglia-derived ASC specks cross-seed amyloid-β in Alzheimer's disease. Nature 552:355–61
    [Google Scholar]
  148. 148. 
    Villemagne VL, Burnham S, Bourgeat P, Brown B, Ellis KA et al. 2013. Amyloid β deposition, neurodegeneration, and cognitive decline in sporadic Alzheimer's disease: a prospective cohort study. Lancet Neurol 12:357–67
    [Google Scholar]
  149. 149. 
    Wang W-Y, Tan M-S, Yu J-T, Tan L 2015. Role of pro-inflammatory cytokines released from microglia in Alzheimer's disease. Ann. Transl. Med. 3:136
    [Google Scholar]
  150. 150. 
    Wang Y, Cella M, Mallinson K, Ulrich JD, Young KL et al. 2015. TREM2 lipid sensing sustains the microglial response in an Alzheimer's disease model. Cell 160:1061–71An early analysis of microglial deficits in amyloid pathology responses from Trem2 knockout mice.
    [Google Scholar]
  151. 151. 
    Webster JA, Gibbs JR, Clarke J, Ray M, Zhang W et al. 2009. Genetic control of human brain transcript expression in Alzheimer disease. Am. J. Hum. Genet. 84:445–58
    [Google Scholar]
  152. 152. 
    Weiner MW, Veitch DP, Aisen PS, Beckett LA, Cairns NJ et al. 2017. The Alzheimer's Disease Neuroimaging Initiative 3: continued innovation for clinical trial improvement. Alzheimers Dement 13:561–71
    [Google Scholar]
  153. 153. 
    Weinhard L, di Bartolomei G, Bolasco G, Machado P, Schieber NL et al. 2018. Microglia remodel synapses by presynaptic trogocytosis and spine head filopodia induction. Nat. Commun. 9:1228
    [Google Scholar]
  154. 154. 
    Wlodarczyk A, Holtman IR, Krueger M, Yogev N, Bruttger J et al. 2017. A novel microglial subset plays a key role in myelinogenesis in developing brain. EMBO J 36:3292–308
    [Google Scholar]
  155. 155. 
    Wong K, Noubade R, Manzanillo P, Ota N, Foreman O et al. 2017. Mice deficient in NRROS show abnormal microglial development and neurological disorders. Nat. Immunol. 18:633–41
    [Google Scholar]
  156. 156. 
    Wyatt SK, Witt T, Barbaro NM, Cohen-Gadol AA, Brewster AL 2017. Enhanced classical complement pathway activation and altered phagocytosis signaling molecules in human epilepsy. Exp. Neurol. 295:184–93
    [Google Scholar]
  157. 157. 
    Wyss-Coray T, Yan F, Lin AH, Lambris JD, Alexander JJ et al. 2002. Prominent neurodegeneration and increased plaque formation in complement-inhibited Alzheimer's mice. PNAS 99:10837–42
    [Google Scholar]
  158. 158. 
    Yeh FL, Hansen DV, Sheng M 2017. TREM2, microglia, and neurodegenerative diseases. Trends Mol. Med. 23:512–33
    [Google Scholar]
  159. 159. 
    Yeh FL, Wang Y, Tom I, Gonzalez LC, Sheng M 2016. TREM2 binds to apolipoproteins, including APOE and CLU/APOJ, and thereby facilitates uptake of amyloid-beta by microglia. Neuron 91:328–40
    [Google Scholar]
  160. 160. 
    Yin C, Ackermann S, Ma Z, Mohanta SK, Zhang C et al. 2019. ApoE attenuates unresolvable inflammation by complex formation with activated C1q. Nat. Med. 25:496–506
    [Google Scholar]
  161. 161. 
    Yu X, Buttgereit A, Lelios I, Utz SG, Cansever D et al. 2017. The cytokine TGF-β promotes the development and homeostasis of alveolar macrophages. Immunity 47:903–12.e4
    [Google Scholar]
  162. 162. 
    Yuan P, Condello C, Keene CD, Wang Y, Bird TD et al. 2016. TREM2 haplodeficiency in mice and humans impairs the microglia barrier function leading to decreased amyloid compaction and severe axonal dystrophy. Neuron 90:724–39
    [Google Scholar]
  163. 163. 
    Zanjani H, Finch CE, Kemper C, Atkinson J, McKeel D et al. 2005. Complement activation in very early Alzheimer disease. Alzheimer Dis. Assoc. Disord. 19:55–66
    [Google Scholar]
  164. 164. 
    Zhang Y, Chen K, Sloan SA, Bennett ML, Scholze AR et al. 2014. An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex. J. Neurosci. 34:11929–47
    [Google Scholar]
  165. 165. 
    Zhang Y, Sloan SA, Clarke LE, Caneda C, Plaza CA et al. 2016. Purification and characterization of progenitor and mature human astrocytes reveals transcriptional and functional differences with mouse. Neuron 89:37–53
    [Google Scholar]
  166. 166. 
    Zhao Y, Wu X, Li X, Jiang LL, Gui X et al. 2018. TREM2 is a receptor for β-amyloid that mediates microglial function. Neuron 97:1023–31.e7
    [Google Scholar]
  167. 167. 
    Zhong L, Wang Z, Wang D, Wang Z, Martens YA et al. 2018. Amyloid-beta modulates microglial responses by binding to the triggering receptor expressed on myeloid cells 2 (TREM2). Mol. Neurodegener. 13:15
    [Google Scholar]
  168. 168. 
    Zöller T, Schneider A, Kleimeyer C, Masuda T, Potru PS et al. 2018. Silencing of TGFβ signalling in microglia results in impaired homeostasis. Nat. Commun. 9:4011
    [Google Scholar]
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