Review Article | Published:

The identity and function of microglia in neurodegeneration

Nature Immunologyvolume 19pages10481058 (2018) | Download Citation

Abstract

The predominant type of immune cell in the brain is the microglia, a type of tissue-resident macrophage. In a variety of neurodegenerative settings, microglia alter their transcriptional profile, morphology and function in similar ways; thus, these activated cells have been called ‘degeneration- or disease-associated microglia’ (DAM). These activated microglia can perform different functions and exert both positive effects and negative effects in different mouse disease models. In humans, mutations in genes expressed in microglia are linked to various neurodegenerative diseases. Here we provide an overview of the common microglial response to neurodegeneration and key contributing pathways; delineate the multifaceted functions of activated microglia spanning various diseases; and discuss insights from the study of human disease-associated genes. We argue that strong evidence from both mouse models and human genetics causally links the function of activated microglia to neurodegeneration.

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References

  1. 1.

    Heneka, M. T., Golenbock, D. T. & Latz, E. Innate immunity in Alzheimer’s disease. Nat. Immunol. 16, 229–236 (2015).

  2. 2.

    Colonna, M. & Butovsky, O. Microglia function in the central nervous system during health and neurodegeneration. Annu. Rev. Immunol. 35, 441–468 (2017).

  3. 3.

    Heppner, F. L., Ransohoff, R. M. & Becher, B. Immune attack: the role of inflammation in Alzheimer disease. Nat. Rev. Neurosci. 16, 358–372 (2015).

  4. 4.

    Prinz, M., Priller, J., Sisodia, S. S. & Ransohoff, R. M. Heterogeneity of CNS myeloid cells and their roles in neurodegeneration. Nat. Neurosci. 14, 1227–1235 (2011).

  5. 5.

    Ginhoux, F. et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330, 841–845 (2010).

  6. 6.

    Ajami, B., Bennett, J. L., Krieger, C., Tetzlaff, W. & Rossi, F. M. V. Local self-renewal can sustain CNS microglia maintenance and function throughout adult life. Nat. Neurosci. 10, 1538–1543 (2007).

  7. 7.

    Tay, T. L. et al. A new fate mapping system reveals context-dependent random or clonal expansion of microglia. Nat. Neurosci. 20, 793–803 (2017).

  8. 8.

    Askew, K. et al. Coupled proliferation and apoptosis maintain the rapid turnover of microglia in the adult brain. Cell Rep. 18, 391–405 (2017).

  9. 9.

    Kierdorf, K. et al. Microglia emerge from erythromyeloid precursors via Pu.1- and Irf8-dependent pathways. Nat. Neurosci. 16, 273–280 (2013).

  10. 10.

    Buttgereit, A. et al. Sall1 is a transcriptional regulator defining microglia identity and function. Nat. Immunol. 17, 1397–1406 (2016).

  11. 11.

    Erny, D. et al. Host microbiota constantly control maturation and function of microglia in the CNS. Nat. Neurosci. 18, 965–977 (2015).

  12. 12.

    Thion, M. S. et al. Microbiome influences prenatal and adult microglia in a sex-specific manner. Cell 172, 500–516 (2018).

  13. 13.

    Gautier, E. L. et al. Gene-expression profiles and transcriptional regulatory pathways that underlie the identity and diversity of mouse tissue macrophages. Nat. Immunol. 13, 1118–1128 (2012).

  14. 14.

    Butovsky, O. et al. Identification of a unique TGF-β-dependent molecular and functional signature in microglia. Nat. Neurosci. 17, 131–143 (2014).

  15. 15.

    Grabert, K. et al. Microglial brain region-dependent diversity and selective regional sensitivities to aging. Nat. Neurosci. 19, 504–516 (2016).

  16. 16.

    Cronk, J. C. et al. Peripherally derived macrophages can engraft the brain independent of irradiation and maintain an identity distinct from microglia. J. Exp. Med 215, 1627–1647 (2018).

  17. 17.

    Bennett, F. C. et al. A combination of ontogeny and CNS environment establishes microglial identity. Neuron 98, 1170–1183 (2018).

  18. 18.

    Itagaki, S., McGeer, P. L., Akiyama, H., Zhu, S. & Selkoe, D. Relationship of microglia and astrocytes to amyloid deposits of Alzheimer disease. J. Neuroimmunol. 24, 173–182 (1989).

  19. 19.

    Zhang, B. et al. Integrated systems approach identifies genetic nodes and networks in late-onset Alzheimer’s disease. Cell 153, 707–720 (2013).

  20. 20.

    Huang, K. L. et al. A common haplotype lowers PU.1 expression in myeloid cells and delays onset of Alzheimer’s disease. Nat. Neurosci. 20, 1052–1061 (2017).

  21. 21.

    Soreq, L. et al. Major shifts in glial regional identity are a transcriptional hallmark of human brain aging. Cell Rep. 18, 557–570 (2017).

  22. 22.

    McGeer, P. L., Itagaki, S., Boyes, B. E. & McGeer, E. G. Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinson’s and Alzheimer’s disease brains. Neurology 38, 1285–1291 (1988).

  23. 23.

    Sapp, E. et al. Early and progressive accumulation of reactive microglia in the Huntington disease brain. J. Neuropathol. Exp. Neurol. 60, 161–172 (2001).

  24. 24.

    Oakley, H. et al. Intraneuronal β-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer’s disease mutations: potential factors in amyloid plaque formation. J. Neurosci. 26, 10129–10140 (2006).

  25. 25.

    Yoshiyama, Y. et al. Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron 53, 337–351 (2007).

  26. 26.

    Main, B. S. et al. Type-1 interferons contribute to the neuroinflammatory response and disease progression of the MPTP mouse model of Parkinson’s disease. Glia 64, 1590–1604 (2016).

  27. 27.

    Hall, E. D., Oostveen, J. A. & Gurney, M. E. Relationship of microglial and astrocytic activation to disease onset and progression in a transgenic model of familial ALS. Glia 23, 249–256 (1998).

  28. 28.

    Orre, M. et al. Isolation of glia from Alzheimer’s mice reveals inflammation and dysfunction. Neurobiol. Aging 35, 2746–2760 (2014).

  29. 29.

    Wang, Y. et al. TREM2 lipid sensing sustains the microglial response in an Alzheimer’s disease model. Cell 160, 1061–1071 (2015).

  30. 30.

    Friedman, B. A. et al. Diverse brain myeloid expression profiles reveal distinct microglial activation states and aspects of Alzheimer’s disease not evident in mouse models. Cell Rep. 22, 832–847 (2018).

  31. 31.

    Chiu, I. M. et al. A neurodegeneration-specific gene-expression signature of acutely isolated microglia from an amyotrophic lateral sclerosis mouse model. Cell Rep. 4, 385–401 (2013).

  32. 32.

    Mathys, H. et al. Temporal tracking of microglia activation in neurodegeneration at single-cell resolution. Cell Rep. 21, 366–380 (2017).

  33. 33.

    Ajami, B. et al. Single-cell mass cytometry reveals distinct populations of brain myeloid cells in mouse neuroinflammation and neurodegeneration models. Nat. Neurosci. 21, 541–551 (2018).

  34. 34.

    Mrdjen, D. et al. High-dimensional single-cell mapping of central nervous system immune cells reveals distinct myeloid subsets in health, aging, and disease. Immunity 48, 380–395.e6 (2018).

  35. 35.

    Holtman, I. R. et al. Induction of a common microglia gene expression signature by aging and neurodegenerative conditions: a co-expression meta-analysis. Acta Neuropathol. Commun. 3, 31 (2015).

  36. 36.

    Keren-Shaul, H. et al. A unique microglia type associated with restricting development of Alzheimer’s disease. Cell 169, 1276–1290 (2017).

  37. 37.

    Rangaraju, S. et al. Identification and therapeutic modulation of a pro-inflammatory subset of disease-associated-microglia in Alzheimer’s disease. Mol. Neurodegener. 13, 24 (2018).

  38. 38.

    Poliani, P. L. et al. TREM2 sustains microglial expansion during aging and response to demyelination. J. Clin. Invest. 125, 2161–2170 (2015).

  39. 39.

    Raj, D. D. A. et al. Priming of microglia in a DNA-repair deficient model of accelerated aging. Neurobiol. Aging 35, 2147–2160 (2014).

  40. 40.

    Krasemann, S. et al. The TREM2-APOE pathway drives the transcriptional phenotype of dysfunctional microglia in neurodegenerative diseases. Immunity 47, 566–581 (2017).

  41. 41.

    Wlodarczyk, A. et al. A novel microglial subset plays a key role in myelinogenesis in developing brain. EMBO J. 36, 3292–3308 (2017).

  42. 42.

    Bruijn, L. I. et al. Aggregation and motor neuron toxicity of an ALS-linked SOD1 mutant independent from wild-type SOD1. Science 281, 1851–1854 (1998).

  43. 43.

    Leyns, C. E. G. et al. TREM2 deficiency attenuates neuroinflammation and protects against neurodegeneration in a mouse model of tauopathy. Proc. Natl. Acad. Sci. USA 114, 11524–11529 (2017).

  44. 44.

    Kang, S. S. et al. Behavioral and transcriptomic analysis of Trem2-null mice: not all knockout mice are created equal. Hum. Mol. Genet. 27, 211–223 (2018).

  45. 45.

    Turnbull, I. R. et al. Cutting edge: TREM-2 attenuates macrophage activation. J. Immunol. 177, 3520–3524 (2006).

  46. 46.

    Ulland, T. K. et al. TREM2 maintains microglial metabolic fitness in Alzheimer’s disease. Cell 170, 649–663 (2017).

  47. 47.

    Kobayashi, M., Konishi, H., Sayo, A., Takai, T. & Kiyama, H. TREM2/DAP12 signal elicits proinflammatory response in microglia and exacerbates neuropathic pain. J. Neurosci. 36, 11138–11150 (2016).

  48. 48.

    Ulrich, J. D. et al. ApoE facilitates the microglial response to amyloid plaque pathology. J. Exp. Med. 215, 1047–1058 (2018).

  49. 49.

    Yeh, F. L., Wang, Y., Tom, I., Gonzalez, L. C. & Sheng, M. TREM2 binds to apolipoproteins, including APOE and CLU/APOJ, and thereby facilitates uptake of amyloid-β by microglia. Neuron 91, 328–340 (2016).

  50. 50.

    Bailey, C. C., DeVaux, L. B. & Farzan, M. The triggering receptor expressed on myeloid cells 2 binds apolipoprotein E. J. Biol. Chem. 290, 26033–26042 (2015).

  51. 51.

    Atagi, Y. et al. Apolipoprotein E Is a ligand for triggering receptor expressed on myeloid cells 2 (TREM2). J. Biol. Chem. 290, 26043–26050 (2015).

  52. 52.

    Otero, K. et al. Macrophage colony-stimulating factor induces the proliferation and survival of macrophages via a pathway involving DAP12 and β-catenin. Nat. Immunol. 10, 734–743 (2009).

  53. 53.

    Weber, G. F., Ashkar, S., Glimcher, M. J. & Cantor, H. Receptor-ligand interaction between CD44 and osteopontin (Eta-1). Science 271, 509–512 (1996).

  54. 54.

    Butovsky, O. et al. Targeting miR-155 restores abnormal microglia and attenuates disease in SOD1 mice. Ann. Neurol. 77, 75–99 (2015).

  55. 55.

    Baruch, K. et al. Aging. Aging-induced type I interferon response at the choroid plexus negatively affects brain function. Science 346, 89–93 (2014).

  56. 56.

    Deczkowska, A. et al. Mef2C restrains microglial inflammatory response and is lost in brain ageing in an IFN-I-dependent manner. Nat. Commun. 8, 717 (2017).

  57. 57.

    Minter, M. R. et al. Deletion of the type-1 interferon receptor in APPSWE/PS1ΔE9 mice preserves cognitive function and alters glial phenotype. Acta Neuropathol. Commun. 4, 72 (2016).

  58. 58.

    Taylor, J. M. et al. Type-1 interferon signaling mediates neuro-inflammatory events in models of Alzheimer’s disease. Neurobiol. Aging 35, 1012–1023 (2014).

  59. 59.

    Yamamoto, M. et al. Interferon-γ and tumor necrosis factor-α regulate amyloid-β plaque deposition and β-secretase expression in Swedish mutant APP transgenic mice. Am. J. Pathol. 170, 680–692 (2007).

  60. 60.

    Mount, M. P. et al. Involvement of interferon-γ in microglial-mediated loss of dopaminergic neurons. J. Neurosci. 27, 3328–3337 (2007).

  61. 61.

    El Khoury, J. B. et al. CD36 mediates the innate host response to β-amyloid. J. Exp. Med. 197, 1657–1666 (2003).

  62. 62.

    Stewart, C. R. et al. CD36 ligands promote sterile inflammation through assembly of a Toll-like receptor 4 and 6 heterodimer. Nat. Immunol. 11, 155–161 (2010).

  63. 63.

    Richard, K. L., Filali, M., Préfontaine, P. & Rivest, S. 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, 5784–5793 (2008).

  64. 64.

    Papageorgiou, I. E. et al. TLR4-activated microglia require IFN-γ to induce severe neuronal dysfunction and death in situ. Proc. Natl. Acad. Sci. USA 113, 212–217 (2016).

  65. 65.

    Tahara, K. et al. Role of toll-like receptor signalling in Aβ uptake and clearance. Brain 129, 3006–3019 (2006).

  66. 66.

    Lim, J. E. et al. MyD88 deficiency ameliorates β-amyloidosis in an animal model of Alzheimer’s disease. Am. J. Pathol. 179, 1095–1103 (2011).

  67. 67.

    Weitz, T. M., Gate, D., Rezai-Zadeh, K. & Town, T. MyD88 is dispensable for cerebral amyloidosis and neuroinflammation in APP/PS1 transgenic mice. Am. J. Pathol. 184, 2855–2861 (2014).

  68. 68.

    Lund, H. et al. Fatal demyelinating disease is induced by monocyte-derived macrophages in the absence of TGF-β signaling. Nat. Immunol. 19, 1–7 (2018).

  69. 69.

    Perez-Nievas, B. G. et al. Dissecting phenotypic traits linked to human resilience to Alzheimer’s pathology. Brain 136, 2510–2526 (2013).

  70. 70.

    Yuan, P. et al. TREM2 haplodeficiency in mice and humans impairs the microglia barrier function leading to decreased amyloid compaction and severe axonal dystrophy. Neuron 90, 724–739 (2016).

  71. 71.

    Wang, Y. et al. TREM2-mediated early microglial response limits diffusion and toxicity of amyloid plaques. J. Exp. Med. 213, 667–675 (2016).

  72. 72.

    Lee, C. Y. D. & Landreth, G. E. The role of microglia in amyloid clearance from the AD brain. J. Neural Transm. 117, 949–960 (2010).

  73. 73.

    Bates, K. A. et al. Clearance mechanisms of Alzheimer’s amyloid-β peptide: implications for therapeutic design and diagnostic tests. Mol. Psychiatry 14, 469–486 (2009).

  74. 74.

    Baranello, R. J. et al. Amyloid-β protein clearance and degradation (ABCD) pathways and their role in Alzheimer’s disease. Curr. Alzheimer Res. 12, 32–46 (2015).

  75. 75.

    Yan, P. et al. Matrix metalloproteinase-9 degrades amyloid-β fibrils in vitro and compact plaques in situ. J. Biol. Chem. 281, 24566–24574 (2006).

  76. 76.

    Iwata, N. et al. Metabolic regulation of brain Aβ by neprilysin. Science 292, 1550–1552 (2001).

  77. 77.

    Qiu, W. Q. et al. Insulin-degrading enzyme regulates extracellular levels of amyloid β-protein by degradation. J. Biol. Chem. 273, 32730–32738 (1998).

  78. 78.

    Zhao, Y. et al. TREM2 is a receptor for β-amyloid that mediates microglial function. Neuron 97, 1023–1031 (2018).

  79. 79.

    Chakrabarty, P. et al. IFN-γ promotes complement expression and attenuates amyloid plaque deposition in amyloid β precursor protein transgenic mice. J. Immunol. 184, 5333–5343 (2010).

  80. 80.

    Chakrabarty, P. et al. Massive gliosis induced by interleukin-6 suppresses Aβ deposition in vivo: evidence against inflammation as a driving force for amyloid deposition. FASEB J. 24, 548–559 (2010).

  81. 81.

    Chakrabarty, P., Herring, A., Ceballos-Diaz, C., Das, P. & Golde, T. E. Hippocampal expression of murine TNFα results in attenuation of amyloid deposition in vivo. Mol. Neurodegener. 6, 16 (2011).

  82. 82.

    Guillot-Sestier, M.-V. et al. Il10 deficiency rebalances innate immunity to mitigate Alzheimer-like pathology. Neuron 85, 534–548 (2015).

  83. 83.

    Chakrabarty, P. et al. IL-10 alters immunoproteostasis in APP mice, increasing plaque burden and worsening cognitive behavior. Neuron 85, 519–533 (2015).

  84. 84.

    Heneka, M. T. et al. NLRP3 is activated in Alzheimer’s disease and contributes to pathology in APP/PS1 mice. Nature 493, 674–678 (2013).

  85. 85.

    Leinenga, G. & Götz, J. Scanning ultrasound removes amyloid-β and restores memory in an Alzheimer’s disease mouse model. Sci. Transl. Med. 7, 278ra33 (2015).

  86. 86.

    Iaccarino, H. F. et al. Gamma frequency entrainment attenuates amyloid load and modifies microglia. Nature 540, 230–235 (2016).

  87. 87.

    Sevigny, J. et al. The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease. Nature 537, 50–56 (2016).

  88. 88.

    Liao, F. et al. Targeting of nonlipidated, aggregated apoE with antibodies inhibits amyloid accumulation. J. Clin. Invest. 128, 2144–2155 (2018).

  89. 89.

    Prokop, S. et al. Impact of peripheral myeloid cells on amyloid-β pathology in Alzheimer’s disease-like mice. J. Exp. Med. 212, 1811–1818 (2015).

  90. 90.

    Varvel, N. H. et al. Replacement of brain-resident myeloid cells does not alter cerebral amyloid-β deposition in mouse models of Alzheimer’s disease. J. Exp. Med. 212, 1803–1809 (2015).

  91. 91.

    Jay, T. R. et al. Disease progression-dependent effects of TREM2 deficiency in a mouse model of Alzheimer’s disease. J. Neurosci. 37, 637–647 (2017).

  92. 92.

    Spangenberg, E. E. et al. Eliminating microglia in Alzheimer’s mice prevents neuronal loss without modulating amyloid-β pathology. Brain 139, 1265–1281 (2016).

  93. 93.

    Sosna, J. et al. 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 (2018).

  94. 94.

    Wu, P. J., Hung, Y. F., Liu, H. Y. & Hsueh, Y. P. Deletion of the inflammasome sensor Aim2 mitigates Aβ deposition and microglial activation but increases inflammatory cytokine expression in an Alzheimer disease mouse model. Neuroimmunomodulation 24, 29–39 (2017).

  95. 95.

    Venegas, C. et al. Microglia-derived ASC specks cross-seed amyloid-β in Alzheimer’s disease. Nature 552, 355–361 (2017).

  96. 96.

    Asai, H. et al. Depletion of microglia and inhibition of exosome synthesis halt tau propagation. Nat. Neurosci. 18, 1584–1593 (2015).

  97. 97.

    Lampron, A. et al. Inefficient clearance of myelin debris by microglia impairs remyelinating processes. J. Exp. Med. 212, 481–495 (2015).

  98. 98.

    Cantoni, C. et al. TREM2 regulates microglial cell activation in response to demyelination in vivo. Acta Neuropathol. 129, 429–447 (2015).

  99. 99.

    Spiller, K. J. et al. Microglia-mediated recovery from ALS-relevant motor neuron degeneration in a mouse model of TDP-43 proteinopathy. Nat. Neurosci. 21, 329–340 (2018).

  100. 100.

    Stevens, B. et al. The classical complement cascade mediates CNS synapse elimination. Cell 131, 1164–1178 (2007).

  101. 101.

    Schafer, D. P. et al. Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron 74, 691–705 (2012).

  102. 102.

    Harrison, J. K. et al. Role for neuronally derived fractalkine in mediating interactions between neurons and CX3CR1-expressing microglia. Proc. Natl. Acad. Sci. USA 95, 10896–10901 (1998).

  103. 103.

    Hoshiko, M., Arnoux, I., Avignone, E., Yamamoto, N. & Audinat, E. Deficiency of the microglial receptor CX3CR1 impairs postnatal functional development of thalamocortical synapses in the barrel cortex. J. Neurosci. 32, 15106–15111 (2012).

  104. 104.

    Filipello, F. et al. The microglial innate immune receptor TREM2 is required for synapse elimination and normal brain connectivity. Immunity 48, 979–991.e8 (2018).

  105. 105.

    Hong, S. et al. Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science 33, 395–401 (2015).

  106. 106.

    Shi, Q. et al. Complement C3-deficient mice fail to display age-related hippocampal decline. J. Neurosci. 35, 13029–13042 (2015).

  107. 107.

    Vasek, M. J. et al. A complement-microglial axis drives synapse loss during virus-induced memory impairment. Nature 534, 538–543 (2016).

  108. 108.

    Singhrao, S. K., Neal, J. W., Morgan, B. P. & Gasque, P. Increased complement biosynthesis by microglia and complement activation on neurons in Huntington’s disease. Exp. Neurol. 159, 362–376 (1999).

  109. 109.

    Bialas, A. R. et al. Microglia-dependent synapse loss in type I interferon-mediated lupus. Nature 546, 539–543 (2017).

  110. 110.

    Crow, Y. J. et al. Mutations in the gene encoding the 3′-5′ DNA exonuclease TREX1 cause Aicardi-Goutières syndrome at the AGS1 locus. Nat. Genet. 38, 917–920 (2006).

  111. 111.

    Goldmann, T. et al. USP18 lack in microglia causes destructive interferonopathy of the mouse brain. EMBO J. 34, 1612–1629 (2015).

  112. 112.

    Meuwissen, M. E. C. et al. Human USP18 deficiency underlies type 1 interferonopathy leading to severe pseudo-TORCH syndrome. J. Exp. Med. 213, 1163–1174 (2016).

  113. 113.

    Fourgeaud, L. et al. TAM receptors regulate multiple features of microglial physiology. Nature 532, 240–244 (2016).

  114. 114.

    Fuhrmann, M. et al. Microglial Cx3cr1 knockout prevents neuron loss in a mouse model of Alzheimer’s disease. Nat. Neurosci. 13, 411–413 (2010).

  115. 115.

    Dagher, N. N. et al. Colony-stimulating factor 1 receptor inhibition prevents microglial plaque association and improves cognition in 3xTg-AD mice. J. Neuroinflammation 12, 139 (2015).

  116. 116.

    Acharya, M. M. et al. Elimination of microglia improves cognitive function following cranial irradiation. Sci. Rep. 6, 31545 (2016).

  117. 117.

    Martínez-Muriana, A. et al. CSF1R blockade slows the progression of amyotrophic lateral sclerosis by reducing microgliosis and invasion of macrophages into peripheral nerves. Sci. Rep. 6, 25663 (2016).

  118. 118.

    Haure-Mirande, J.-V. et al. Deficiency of TYROBP, an adapter protein for TREM2 and CR3 receptors, is neuroprotective in a mouse model of early Alzheimer’s pathology. Acta Neuropathol. 134, 769–788 (2017).

  119. 119.

    Qin, Y. et al. A milieu molecule for TGF-β required for microglia function in the nervous system. Cell 174, 156–171.e16 (2018).

  120. 120.

    Wong, K. et al. Mice deficient in NRROS show abnormal microglial development and neurological disorders. Nat. Immunol. 18, 633–641 (2017).

  121. 121.

    Mass, E. et al. A somatic mutation in erythro-myeloid progenitors causes neurodegenerative disease. Nature 549, 389–393 (2017).

  122. 122.

    Brambilla, R. et al. Inhibition of astroglial nuclear factor κB reduces inflammation and improves functional recovery after spinal cord injury. J. Exp. Med. 202, 145–156 (2005).

  123. 123.

    Reichenbach, N. et al. P2Y1 receptor blockade normalizes network dysfunction and cognition in an Alzheimer’s disease model. J. Exp. Med. 215, 1649–1663 (2018).

  124. 124.

    Liddelow, S. A. et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature 541, 481–487 (2017).

  125. 125.

    Yun, S. P. et al. Block of A1 astrocyte conversion by microglia is neuroprotective in models of Parkinson’s disease. Nat. Med. 24, 931–938, https://doi.org/10.1038/s41591-018-0051-5 (2018).

  126. 126.

    Paloneva, J. et al. Mutations in two genes encoding different subunits of a receptor signaling complex result in an identical disease phenotype. Am. J. Hum. Genet. 71, 656–662 (2002).

  127. 127.

    Cella, M. et al. Impaired differentiation of osteoclasts in TREM-2-deficient individuals. J. Exp. Med. 198, 645–651 (2003).

  128. 128.

    Pridans, C., Sauter, K. A., Baer, K., Kissel, H. & Hume, D. A. CSF1R mutations in hereditary diffuse leukoencephalopathy with spheroids are loss of function. Sci. Rep. 3, 3013 (2013).

  129. 129.

    Rademakers, R. et al. Mutations in the colony stimulating factor 1 receptor (CSF1R) gene cause hereditary diffuse leukoencephalopathy with spheroids. Nat. Genet. 44, 200–205 (2011).

  130. 130.

    Tada, M. et al. Characteristic microglial features in patients with hereditary diffuse leukoencephalopathy with spheroids. Ann. Neurol. 80, 554–565 (2016).

  131. 131.

    Lambert, J.-C. et al. Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer’s disease. Nat. Genet. 41, 1094–1099 (2009).

  132. 132.

    Hollingworth, P. et al. Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer’s disease. Nat. Genet. 43, 429–435 (2011).

  133. 133.

    Lambert, J. C. et al. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease. Nat. Genet. 45, 1452–1458 (2013).

  134. 134.

    Guerreiro, R. et al. TREM2 variants in Alzheimer’s disease. N. Engl. J. Med. 368, 117–127 (2013).

  135. 135.

    Jonsson, T. et al. Variant of TREM2 associated with the risk of Alzheimer’s disease. N. Engl. J. Med. 368, 107–116 (2013).

  136. 136.

    Jin, S. C. et al. Coding variants in TREM2 increase risk for Alzheimer’s disease. Hum. Mol. Genet. 23, 5838–5846 (2014).

  137. 137.

    Sims, R. et al. Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer’s disease. Nat. Genet. 49, 1373–1384 (2017).

  138. 138.

    Jiang, T. et al. A rare coding variant in TREM2 increases risk for Alzheimer’s disease in Han Chinese. Neurobiol. Aging 42, 217.e1–217.e3 (2016).

  139. 139.

    Pottier, C. et al. TYROBP genetic variants in early-onset Alzheimer’s disease. Neurobiol. Aging 48, 222.e9–222.e15 (2016).

  140. 140.

    Song, W. et al. Alzheimer's disease-associated TREM2 variants exhibit either decreased or increased ligand-dependent activation. Alzheimers Dement. 13, 381–387 (2017).

  141. 141.

    Kober, D. L. et al. Neurodegenerative disease mutations in TREM2 reveal a functional surface and distinct loss-of-function mechanisms. eLife 5, 707–720 (2016).

  142. 142.

    Sudom, A. et al. Molecular basis for the loss-of-function effects of the Alzheimer’s disease-associated R47H variant of the immune receptor TREM2. J. Biol. Chem. 293, 12634–12646 (2018).

  143. 143.

    Song, W. M. et al. Humanized TREM2 mice reveal microglia-intrinsic and -extrinsic effects of R47H polymorphism. J. Exp. Med. 215, 745–760 (2018).

  144. 144.

    Rebeck, G. W., Reiter, J. S., Strickland, D. K. & Hyman, B. T. Apolipoprotein E in sporadic Alzheimer’s disease: allelic variation and receptor interactions. Neuron 11, 575–580 (1993).

  145. 145.

    Shi, Y. et al. ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy. Nature 549, 523–527 (2017).

  146. 146.

    Rosen, D. R. et al. Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 362, 59–62 (1993).

  147. 147.

    Pramatarova, A., Laganière, J., Roussel, J., Brisebois, K. & Rouleau, G. A. Neuron-specific expression of mutant superoxide dismutase 1 in transgenic mice does not lead to motor impairment. J. Neurosci. 21, 3369–3374 (2001).

  148. 148.

    Boillée, S. et al. Onset and progression in inherited ALS determined by motor neurons and microglia. Science 312, 1389–1392 (2006).

  149. 149.

    Beers, D. R. et al. Wild-type microglia extend survival in PU.1 knockout mice with familial amyotrophic lateral sclerosis. Proc. Natl. Acad. Sci. USA 103, 16021–16026 (2006).

  150. 150.

    Haeusler, A. R. et al. C9orf72 nucleotide repeat structures initiate molecular cascades of disease. Nature 507, 195–200 (2014).

  151. 151.

    Mori, K. et al. The C9orf72 GGGGCC repeat is translated into aggregating dipeptide-repeat proteins in FTLD/ALS. Science 339, 1335–1338 (2013).

  152. 152.

    DeJesus-Hernandez, M. et al. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 72, 245–256 (2011).

  153. 153.

    Renton, A. E. et al. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 72, 257–268 (2011).

  154. 154.

    O’Rourke, J. G. et al. C9orf72 is required for proper macrophage and microglial function in mice. Science 351, 1324–1329 (2016).

  155. 155.

    Freischmidt, A. et al. Haploinsufficiency of TBK1 causes familial ALS and fronto-temporal dementia. Nat. Neurosci. 18, 631–636 (2015).

  156. 156.

    Van Damme, P. et al. Progranulin functions as a neurotrophic factor to regulate neurite outgrowth and enhance neuronal survival. J. Cell Biol. 181, 37–41 (2008).

  157. 157.

    Tanaka, Y. et al. Progranulin regulates lysosomal function and biogenesis through acidification of lysosomes. Hum. Mol. Genet. 26, 969–988 (2017).

  158. 158.

    Baker, M. et al. Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17. Nature 442, 916–919 (2006).

  159. 159.

    Cruts, M. et al. Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21. Nature 442, 920–924 (2006).

  160. 160.

    Yin, F. et al. Exaggerated inflammation, impaired host defense, and neuropathology in progranulin-deficient mice. J. Exp. Med. 207, 117–128 (2010).

  161. 161.

    Lui, H. et al. Progranulin deficiency promotes circuit-specific synaptic pruning by microglia via complement activation. Cell 165, 921–935 (2016).

  162. 162.

    Martens, L. H. et al. Progranulin deficiency promotes neuroinflammation and neuron loss following toxin-induced injury. J. Clin. Invest. 122, 3955–3959 (2012).

  163. 163.

    Minami, S. S. et al. Progranulin protects against amyloid b deposition and toxicity in Alzheimer’s disease mouse models. Nat. Med. 20, 1157–1164 (2014).

  164. 164.

    Hamza, T. H. et al. Common genetic variation in the HLA region is associated with late-onset sporadic Parkinson’s disease. Nat. Genet. 42, 781–785 (2010).

  165. 165.

    Goedert, M. Alpha-synuclein and neurodegenerative diseases. Nat. Rev. Neurosci. 2, 492–501 (2001).

  166. 166.

    Polymeropoulos, M. H. et al. Mutation in the a-synuclein gene identified in families with Parkinson’s disease. Science 276, 2045–2047 (1997).

  167. 167.

    Zhang, W. et al. Aggregated a-synuclein activates microglia: a process leading to disease progression in Parkinson’s disease. FASEB J. 19, 533–542 (2005).

  168. 168.

    MacDonald, M. E. et al. The Huntington’s Disease Collaborative Research Group. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. Cell 72, 971–983 (1993).

  169. 169.

    Ross, C. A. & Tabrizi, S. J. Huntington’s disease: from molecular pathogenesis to clinical treatment. Lancet Neurol. 10, 83–98 (2011).

  170. 170.

    Björkqvist, M. et al. A novel pathogenic pathway of immune activation detectable before clinical onset in Huntington’s disease. J. Exp. Med. 205, 1869–1877 (2008).

  171. 171.

    Crotti, A. et al. Mutant Huntingtin promotes autonomous microglia activation via myeloid lineage-determining factors. Nat. Neurosci. 17, 513–521 (2014).

  172. 172.

    Galatro, T. F. et al. Transcriptomic analysis of purified human cortical microglia reveals age-associated changes. Nat. Neurosci. 20, 1162–1171 (2017).

  173. 173.

    Gosselin, D. et al. An environment-dependent transcriptional network specifies human microglia identity. Science 356, 1248–1259 (2017).

  174. 174.

    Olah, M. et al. A transcriptomic atlas of aged human microglia. Nat. Commun. 9, 539 (2018).

  175. 175.

    Smith, A. M. & Dragunow, M. The human side of microglia. Trends Neurosci. 37, 125–135 (2014).

  176. 176.

    Streit, W. J., Braak, H., Xue, Q.-S. & Bechmann, I. Dystrophic (senescent) rather than activated microglial cells are associated with tau pathology and likely precede neurodegeneration in Alzheimer’s disease. Acta Neuropathol. 118, 475–485 (2009).

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  1. Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO, USA

    • Wilbur M. Song
    •  & Marco Colonna

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The authors declare no competing interests.

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https://doi.org/10.1038/s41590-018-0212-1