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Interplay between innate immunity and Alzheimer disease: APOE and TREM2 in the spotlight

Nature Reviews Immunology (2018) | Download Citation

Abstract

Alzheimer disease is more than a pure proteopathy. Chronic neuroinflammation stands out during the pathogenesis of the disease and in turn modulates disease progression. The central nervous system (CNS) is separated from the blood circulation by the blood–brain barrier. In Alzheimer disease, neuroinflammation heavily relies on innate immune responses that are primarily mediated by CNS-resident microglia. APOE (which encodes apolipoprotein E) is the strongest genetic risk factor for Alzheimer disease, and APOE was recently shown to affect the disease in part through its immunomodulatory function. This function of APOE is likely linked to triggering receptor expressed on myeloid cells 2 (TREM2), which is expressed by microglia in the CNS. Here, we review the rapidly growing literature on the role of disease-associated microglia, TREM2 and APOE in the pathogenesis of Alzheimer disease and present an integrated view of innate immune function in Alzheimer disease.

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References

  1. 1.

    Alzheimer, A. Über eine eigenartige Erkrankung der Hirnrinde. Allg. Z. Psychiatr. 64, 146–148 (1907).

  2. 2.

    Jack, C. R. Jr. et al. Hypothetical model of dynamic biomarkers of the Alzheimer’s pathological cascade. Lancet Neurol. 9, 119–128 (2010).

  3. 3.

    Bateman, R. J. et al. Clinical and biomarker changes in dominantly inherited Alzheimer’s disease. N. Engl. J. Med. 367, 795–804 (2012).

  4. 4.

    Hardy, J. & Selkoe, D. J. The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 297, 353–356 (2002).

  5. 5.

    Holtzman, D. M., Morris, J. C. & Goate, A. M. Alzheimer’s disease: the challenge of the second century. Sci. Transl Med. 3, 77sr71 (2011).

  6. 6.

    Pimenova, A. A., Raj, T. & Goate, A. M. Untangling genetic risk for Alzheimer’s disease. Biol. Psychiatry 83, 300–310 (2017).

  7. 7.

    Gjoneska, E. et al. Conserved epigenomic signals in mice and humans reveal immune basis of Alzheimer’s disease. Nature 518, 365–369 (2015).

  8. 8.

    Brown, G. C. & Neher, J. J. Microglial phagocytosis of live neurons. Nat. Rev. Neurosci. 15, 209–216 (2014).

  9. 9.

    Liddelow, S. A. et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature 541, 481–487 (2017). This study defines the roles of A1 astrocytes in neurodegenerative diseases and demonstrates an essential role of microglia–astrocytes crosstalk in A1 astrocytic activation.

  10. 10.

    Kaushal, V. et al. Neuronal NLRP1 inflammasome activation of Caspase-1 coordinately regulates inflammatory interleukin-1-β production and axonal degeneration-associated caspase-6 activation. Cell Death Differ. 22, 1676–1686 (2015).

  11. 11.

    Tan, M. S. et al. Amyloid-β induces NLRP1-dependent neuronal pyroptosis in models of Alzheimer’s disease. Cell Death Dis. 5, e1382 (2014).

  12. 12.

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

  13. 13.

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

  14. 14.

    Paolicelli, R. C. et al. Synaptic pruning by microglia is necessary for normal brain development. Science 333, 1456–1458 (2011).

  15. 15.

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

  16. 16.

    Cunningham, C. L., Martinez-Cerdeno, V. & Noctor, S. C. Microglia regulate the number of neural precursor cells in the developing cerebral cortex. J. Neurosci. 33, 4216–4233 (2013).

  17. 17.

    Wakselman, S. et al. Developmental neuronal death in hippocampus requires the microglial CD11b integrin and DAP12 immunoreceptor. J. Neurosci. 28, 8138–8143 (2008).

  18. 18.

    Marin-Teva, J. L. et al. Microglia promote the death of developing Purkinje cells. Neuron 41, 535–547 (2004).

  19. 19.

    Davalos, D. et al. ATP mediates rapid microglial response to local brain injury in vivo. Nat. Neurosci. 8, 752–758 (2005).

  20. 20.

    Nimmerjahn, A., Kirchhoff, F. & Helmchen, F. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308, 1314–1318 (2005).

  21. 21.

    Kettenmann, H., Hanisch, U.-K., Noda, M. & Verkhratsky, A. Physiology of microglia. Physiol. Rev. 91, 461–553 (2011).

  22. 22.

    Wu, Y., Dissing-Olesen, L., MacVicar, B. A. & Stevens, B. Microglia: dynamic mediators of synapse development and plasticity. Trends Immunol. 36, 605–613 (2015).

  23. 23.

    Martinez, F. O. & Gordon, S. The M1 and M2 paradigm of macrophage activation: time for reassessment. F1000Prime Rep. 6, 13 (2014).

  24. 24.

    Boche, D., Perry, V. H. & Nicoll, J. A. Review: activation patterns of microglia and their identification in the human brain. Neuropathol. Appl. Neurobiol. 39, 3–18 (2013).

  25. 25.

    Mosser, D. M. & Edwards, J. P. Exploring the full spectrum of macrophage activation. Nat. Rev. Immunol. 8, 958–969 (2008).

  26. 26.

    Murray, P. J. et al. Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity 41, 14–20 (2014).

  27. 27.

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

  28. 28.

    Krasemann, S. et al. The TREM2-APOE pathway drives the transcriptional phenotype of dysfunctional microglia in neurodegenerative diseases. Immunity 47, 566–581 (2017). This work and reference 27 raise the concept of a neurodegenerative microglial phenotype. They define the molecular signatures of the phenotype and demonstrate the requirement of TREM2 and APOE for its activation.

  29. 29.

    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).

  30. 30.

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

  31. 31.

    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).

  32. 32.

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

  33. 33.

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

  34. 34.

    Chakrabarty, P. et al. Hippocampal expression of murine IL-4 results in exacerbation of amyloid deposition. Mol. Neurodegener. 7, 36 (2012).

  35. 35.

    Vom Berg, J. et al. Inhibition of IL-12/IL-23 signaling reduces Alzheimer’s disease-like pathology and cognitive decline. Nat. Med. 18, 1812–1819 (2012).

  36. 36.

    Kiyota, T. et al. CNS expression of anti-inflammatory cytokine interleukin-4 attenuates Alzheimer’s disease-like pathogenesis in APP+PS1 bigenic mice. FASEB J. 24, 3093–3102 (2010).

  37. 37.

    Qiao, X., Cummins, D. J. & Paul, S. M. Neuroinflammation-induced acceleration of amyloid deposition in the APPV717F transgenic mouse. Eur. J. Neurosci. 14, 474–482 (2001).

  38. 38.

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

  39. 39.

    Grathwohl, S. A. et al. Formation and maintenance of Alzheimer’s disease β-amyloid plaques in the absence of microglia. Nat. Neurosci. 12, 1361–1363 (2009).

  40. 40.

    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).

  41. 41.

    Venegas, C. et al. Microglia-derived ASC specks cross-seed amyloid-β in Alzheimer’s disease. Nature 552, 355–361 (2017). This work shows that activated microglia promote amyloid-β seeding via secreting adaptor protein ASC specks that cross-seed amyloid-β. This study together with reference 39 suggests that microglia participate in the initiation stage of plaque formation by affecting amyloid-β seeding.

  42. 42.

    Baik, S. H., Kang, S., Son, S. M. & Mook-Jung, I. Microglia contributes to plaque growth by cell death due to uptake of amyloid β in the brain of Alzheimer’s disease mouse model. Glia 64, 2274–2290 (2016).

  43. 43.

    Yin, Z. et al. Immune hyperreactivity of Aβ plaque-associated microglia in Alzheimer’s disease. Neurobiol. Aging 55, 115–122 (2017).

  44. 44.

    Ulrich, J. D. et al. Altered microglial response to Aβ plaques in APPPS1-21 mice heterozygous for TREM2. Mol. Neurodegener. 9, 20 (2014).

  45. 45.

    Jay, T. R. et al. TREM2 deficiency eliminates TREM2+ inflammatory macrophages and ameliorates pathology in Alzheimer’s disease mouse models. J. Exp. Med. 212, 287–295 (2015).

  46. 46.

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

  47. 47.

    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). References 44–47 show that TREM2 promotes microglial clustering around amyloid-β plaques and demonstrate a disease stage-dependent effect of TREM2 deficiency on amyloid-β pathology.

  48. 48.

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

  49. 49.

    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). References 48 and 49 demonstrate a major TREM2-dependent function of plaque-associated microglia to trim and compact plaques and to serve as a barrier to reduce neuritic dystrophy.

  50. 50.

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

  51. 51.

    Zhang, Y. et al. An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex. J. Neurosci. 34, 11929–11947 (2014).

  52. 52.

    Lee, C. Y. D. et al. Elevated TREM2 gene dosage reprograms microglia responsivity and ameliorates pathological phenotypes in Alzheimer’s disease models. Neuron 97, 1032–1048 (2018).

  53. 53.

    Yamada, K. et al. In vivo microdialysis reveals age-dependent decrease of brain interstitial fluid tau levels in P301S human tau transgenic mice. J. Neurosci. 31, 13110–13117 (2011).

  54. 54.

    Clavaguera, F., Hench, J., Goedert, M. & Tolnay, M. Invited review: Prion-like transmission and spreading of tau pathology. Neuropathol. Appl. Neurobiol. 41, 47–58 (2015).

  55. 55.

    Takeda, S. et al. Neuronal uptake and propagation of a rare phosphorylated high-molecular-weight tau derived from Alzheimer’s disease brain. Nat. Commun. 6, 8490 (2015).

  56. 56.

    Bolos, M. et al. Direct evidence of internalization of tau by microglia in vitro and in vivo. J. Alzheimers Dis. 50, 77–87 (2016).

  57. 57.

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

  58. 58.

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

  59. 59.

    Kitazawa, M., Oddo, S., Yamasaki, T. R., Green, K. N. & LaFerla, F. M. Lipopolysaccharide-induced inflammation exacerbates tau pathology by a cyclin-dependent kinase 5-mediated pathway in a transgenic model of Alzheimer’s disease. J. Neurosci. 25, 8843–8853 (2005).

  60. 60.

    Li, Y., Liu, L., Barger, S. W. & Griffin, W. S. Interleukin-1 mediates pathological effects of microglia on tau phosphorylation and on synaptophysin synthesis in cortical neurons through a p38-MAPK pathway. J. Neurosci. 23, 1605–1611 (2003).

  61. 61.

    Kitazawa, M. et al. Blocking IL-1 signaling rescues cognition, attenuates tau pathology, and restores neuronal β-catenin pathway function in an Alzheimer’s disease model. J. Immunol. 187, 6539–6549 (2011).

  62. 62.

    Bhaskar, K. et al. Regulation of tau pathology by the microglial fractalkine receptor. Neuron 68, 19–31 (2010).

  63. 63.

    Maphis, N. et al. Reactive microglia drive tau pathology and contribute to the spreading of pathological tau in the brain. Brain 138, 1738–1755 (2015).

  64. 64.

    Nash, K. R. et al. Fractalkine overexpression suppresses tau pathology in a mouse model of tauopathy. Neurobiol. Aging 34, 1540–1548 (2013).

  65. 65.

    Bemiller, S. M. et al. TREM2 deficiency exacerbates tau pathology through dysregulated kinase signaling in a mouse model of tauopathy. Mol. Neurodegener. 12, 74 (2017).

  66. 66.

    Jiang, T. et al. Silencing of TREM2 exacerbates tau pathology, neurodegenerative changes, and spatial learning deficits in P301S tau transgenic mice. Neurobiol. Aging 36, 3176–3186 (2015).

  67. 67.

    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). This work shows that dampening neurodegenerative microglial activation via TREM2 deletion reduces neurodegeneration at an advanced disease stage in a tauopathy mouse model, supporting a role of microglia in modulating neurodegeneration.

  68. 68.

    Jiang, T. et al. TREM2 modifies microglial phenotype and provides neuroprotection in P301S tau transgenic mice. Neuropharmacology 105, 196–206 (2016).

  69. 69.

    Shi, Y. et al. ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy. Nature 549, 523–527 (2017). This study demonstrates an amyloid-β-independent role of APOE in regulating neurodegeneration and neuroinflammation in the setting of a tauopathy. The protective effect of APOE deficiency on neurodegeneration is in line with that of TREM2.

  70. 70.

    Kraft, A. W. et al. Attenuating astrocyte activation accelerates plaque pathogenesis in APP/PS1 mice. FASEB J. 27, 187–198 (2013).

  71. 71.

    Liddelow, S. A. & Barres, B. A. Reactive astrocytes: production, function, and therapeutic potential. Immunity 46, 957–967 (2017).

  72. 72.

    Zhang, Y. & Barres, B. A. Astrocyte heterogeneity: an underappreciated topic in neurobiology. Curr. Opin. Neurobiol. 20, 588–594 (2010).

  73. 73.

    Vainchtein, I. D. et al. Astrocyte-derived interleukin-33 promotes microglial synapse engulfment and neural circuit development. Science 359, 1269–1273 (2018).

  74. 74.

    Chung, W. S. et al. Astrocytes mediate synapse elimination through MEGF10 and MERTK pathways. Nature 504, 394–400 (2013).

  75. 75.

    Chung, W. S. et al. Novel allele-dependent role for APOE in controlling the rate of synapse pruning by astrocytes. Proc. Natl Acad. Sci. USA 113, 10186–10191 (2016).

  76. 76.

    Sofroniew, M. V. Astrocyte barriers to neurotoxic inflammation. Nat. Rev. Neurosci. 16, 249–263 (2015).

  77. 77.

    Zamanian, J. L. et al. Genomic analysis of reactive astrogliosis. J. Neurosci. 32, 6391–6410 (2012).

  78. 78.

    Lian, H. et al. NFκB-activated astroglial release of complement C3 compromises neuronal morphology and function associated with Alzheimer’s disease. Neuron 85, 101–115 (2015).

  79. 79.

    Lian, H. et al. Astrocyte-microglia cross talk through complement activation modulates amyloid pathology in mouse models of Alzheimer’s disease. J. Neurosci. 36, 577–589 (2016).

  80. 80.

    Li, Q. & Barres, B. A. Microglia and macrophages in brain homeostasis and disease. Nat. Rev. Immunol. 18, 225–242 (2017).

  81. 81.

    Varvel, N. H. et al. Microglial repopulation model reveals a robust homeostatic process for replacing CNS myeloid cells. Proc. Natl Acad. Sci. USA 109, 18150–18155 (2012).

  82. 82.

    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).

  83. 83.

    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).

  84. 84.

    Michaud, J. P., Bellavance, M. A., Prefontaine, P. & Rivest, S. Real-time in vivo imaging reveals the ability of monocytes to clear vascular amyloid β. Cell Rep. 5, 646–653 (2013).

  85. 85.

    Baik, S. H. et al. Migration of neutrophils targeting amyloid plaques in Alzheimer’s disease mouse model. Neurobiol. Aging 35, 1286–1292 (2014).

  86. 86.

    Zenaro, E. et al. Neutrophils promote Alzheimer’s disease-like pathology and cognitive decline via LFA-1 integrin. Nat. Med. 21, 880–886 (2015).

  87. 87.

    Kumar, D. K. et al. Amyloid-β peptide protects against microbial infection in mouse and worm models of Alzheimer’s disease. Sci. Transl Med. 8, 340ra372 (2016).

  88. 88.

    Holtzman, D. M., Herz, J. & Bu, G. Apolipoprotein E and apolipoprotein E receptors: normal biology and roles in Alzheimer disease. Cold Spring Harbor Persp. Med. 2, a006312 (2012).

  89. 89.

    Bu, G. Apolipoprotein E and its receptors in Alzheimer’s disease: pathways, pathogenesis and therapy. Nat. Rev. Neurosci. 10, 333–344 (2009).

  90. 90.

    Boyles, J. K., Pitas, R. E., Wilson, E., Mahley, R. W. & Taylor, J. M. Apolipoprotein E associated with astrocytic glia of the central nervous system and with nonmyelinating glia of the peripheral nervous system. J. Clin. Invest. 76, 1501–1513 (1985).

  91. 91.

    Uchihara, T. et al. ApoE immunoreactivity and microglial cells in Alzheimer’s disease brain. Neurosci. Lett. 195, 5–8 (1995).

  92. 92.

    Corder, E. H. et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 261, 921–923 (1993).

  93. 93.

    Schmechel, D. E. et al. Increased amyloid β-peptide deposition in cerebral cortex as a consequence of apolipoprotein E genotype in late-onset Alzheimer disease. Proc. Natl Acad. Sci. USA 90, 9649–9653 (1993).

  94. 94.

    Agosta, F. et al. Apolipoprotein E ε4 is associated with disease-specific effects on brain atrophy in Alzheimer’s disease and frontotemporal dementia. Proc. Natl Acad. Sci. USA 106, 2018–2022 (2009).

  95. 95.

    Strittmatter, W. J. et al. Apolipoprotein E: high-avidity binding to β-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc. Natl Acad. Sci. USA 90, 1977–1981 (1993).

  96. 96.

    Bales, K. R. et al. Lack of apolipoprotein E dramatically reduces amyloid β-peptide deposition. Nat. Genet. 17, 263–264 (1997).

  97. 97.

    Kim, J. et al. Haploinsufficiency of human APOE reduces amyloid deposition in a mouse model of amyloid-β amyloidosis. J. Neurosci. 31, 18007–18012 (2011).

  98. 98.

    Holtzman, D. M. et al. Apolipoprotein E isoform-dependent amyloid deposition and neuritic degeneration in a mouse model of Alzheimer’s disease. Proc. Natl Acad. Sci. USA 97, 2892–2897 (2000).

  99. 99.

    Fagan, A. M. et al. Human and murine ApoE markedly alters Aβ metabolism before and after plaque formation in a mouse model of Alzheimer’s disease. Neurobiol. Dis. 9, 305–318 (2002).

  100. 100.

    Castellano, J. M. et al. Human apoE isoforms differentially regulate brain amyloid-peptide clearance. Sci. Transl Med. 3, 89ra57 (2011).

  101. 101.

    Huynh, T. V., Davis, A. A., Ulrich, J. D. & Holtzman, D. M. Apolipoprotein E and Alzheimer’s disease: the influence of apolipoprotein E on amyloid-β and other amyloidogenic proteins. J. Lipid Res. 58, 824–836 (2017).

  102. 102.

    Strittmatter, W. J. et al. Isoform-specific interactions of apolipoprotein E with microtubule-associated protein tau: implications for Alzheimer disease. Proc. Natl Acad. Sci. USA 91, 11183–11186 (1994).

  103. 103.

    Fleming, L. M., Weisgraber, K. H., Strittmatter, W. J., Troncoso, J. C. & Johnson, G. V. W. Differential binding of apolipoprotein E isoforms to tau and other cytoskeletal proteins. Exp. Neurol. 138, 252–260 (1996).

  104. 104.

    Mishra, A. et al. Gene-based association studies report genetic links for clinical subtypes of frontotemporal dementia. Brain 140, 1437–1446 (2017).

  105. 105.

    Tsuang, D. et al. APOE ε4 increases risk for dementia in pure synucleinopathies. JAMA Neurol. 70, 223–228 (2013).

  106. 106.

    Gallardo, G., Schluter, O. M. & Sudhof, T. C. A molecular pathway of neurodegeneration linking α-synuclein to ApoE and Aβ peptides. Nat. Neurosci. 11, 301–308 (2008).

  107. 107.

    Shin, S. et al. Apolipoprotein E mediation of neuro-inflammation in a murine model of multiple sclerosis. J. Neuroimmunol. 271, 8–17 (2014).

  108. 108.

    Gale, S. C. et al. APOE4 is associated with enhanced in vivo innate immune responses in human subjects. J. Allergy Clin. Immunol. 134, 127–134 (2014).

  109. 109.

    Vitek, M. P., Brown, C. M. & Colton, C. A. APOE genotype-specific differences in the innate immune response. Neurobiol. Aging 30, 1350–1360 (2009).

  110. 110.

    Zhu, Y. et al. APOE genotype alters glial activation and loss of synaptic markers in mice. Glia 60, 559–569 (2012).

  111. 111.

    Fessler, M. B. & Parks, J. S. Intracellular lipid flux and membrane microdomains as organizing principles in inflammatory cell signaling. J. Immunol. 187, 1529–1535 (2011).

  112. 112.

    Yvan-Charvet, L. et al. ATP-binding cassette transporters and HDL suppress hematopoietic stem cell proliferation. Science 328, 1689–1693 (2010).

  113. 113.

    Murphy, A. J. et al. ApoE regulates hematopoietic stem cell proliferation, monocytosis, and monocyte accumulation in atherosclerotic lesions in mice. J. Clin. Invest. 121, 4138–4149 (2011).

  114. 114.

    Okoro, E. U. et al. Apolipoprotein E4 is deficient in inducing macrophage ABCA1 expression and stimulating the Sp1 signaling pathway. PLoS ONE 7, e44430 (2012).

  115. 115.

    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). This work demonstrates that APOE is a receptor for TREM2 and shows that APOE binds to apoptotic neuronal cell surfaces and increases TREM2-mediated phagocytosis by microglia in vitro, supporting the APOE opsonization hypothesis.

  116. 116.

    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).

  117. 117.

    Jendresen, C., Arskog, V., Daws, M. R. & Nilsson, L. N. The Alzheimer’s disease risk factors apolipoprotein E and TREM2 are linked in a receptor signaling pathway. J. Neuroinflamm. 14, 59 (2017).

  118. 118.

    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).

  119. 119.

    Ulrich, J. D. et al. ApoE facilitates the microglial response to amyloid plaque pathology. J. Exp. Med. 215, 1047–1058 (2018). This work demonstrates that APOE is required for microglial association with plaques to perform a plaque-trimming function similar to that of TREM2, supporting an APOE–TREM2 axis in mediating microglial function.

  120. 120.

    Huynh, T. V. et al. Age-dependent effects of apoE reduction using antisense oligonucleotides in a model of β-amyloidosis. Neuron 96, 1013–1023 (2017).

  121. 121.

    Liu, C. C. et al. ApoE4 accelerates early seeding of amyloid pathology. Neuron 96, 1024–1032 (2017). References 121 and 122 show that APOE is essential for plaque formation during the initial seeding stage.

  122. 122.

    Namba, Y., Tomonaga, M., Kawasaki, H., Otomo, E. & Ikeda, K. Apolipoprotein E immunoreactivity in cerebral amyloid deposits and neurofibrillary tangles in Alzheimer’s disease and kuru plaque amyloid in Creutzfeldt-Jakob disease. Brain Res. 541, 163–166 (1991).

  123. 123.

    Wisniewski, T. & Frangione, B. Apolipoprotein E: a pathological chaperone protein in patients with cerebral and systemic amyloid. Neurosci. Lett. 135, 235–238 (1992).

  124. 124.

    Rodriguez, G.a., Tai, L. M., LaDu, M. J. & Rebeck, G. W. Human APOE4 increases microglia reactivity at Aβ plaques in a mouse model of Aβ deposition. J. Neuroinflamm. 11, 111–111 (2014).

  125. 125.

    Huang, Y. et al. Apolipoprotein E fragments present in Alzheimer’s disease brains induce neurofibrillary tangle-like intracellular inclusions in neurons. Proc. Natl Acad. Sci. USA 98, 8838–8843 (2001).

  126. 126.

    Farrer, L. A. et al. Allele ε4 of apolipoprotein E shows a dose effect on age at onset of Pick disease. Exp. Neurol. 136, 162–170 (1995).

  127. 127.

    Brecht, W. J. Neuron-specific apolipoprotein E4 proteolysis is associated with increased tau phosphorylation in brains of transgenic mice. J. Neurosci. 24, 2527–2534 (2004).

  128. 128.

    Harris, F. M., Brecht, W. J., Xu, Q., Mahley, R. W. & Huang, Y. Increased tau phosphorylation in apolipoprotein E4 transgenic mice is associated with activation of extracellular signal-regulated kinase: modulation by zinc. J. Biol. Chem. 279, 44795–44801 (2004).

  129. 129.

    Zhou, M. et al. APOE4 induces site-specific tau phosphorylation through calpain-CDK5 signaling pathway in EFAD-Tg mice. Curr. Alzheimer Res. 13, 1048–1055 (2016).

  130. 130.

    Pericak-Vance, M. A. et al. Linkage studies in familial Alzheimer disease: evidence for chromosome 19 linkage. Am. J. Hum. Genet. 48, 1034–1050 (1991).

  131. 131.

    Neyen, C. D. & Gordon, S. in eLS (John Wiley & Sons, Ltd, 2001).

  132. 132.

    de Jong, A. Activation of human T cells by CD1 and self-lipids. Immunol. Rev. 267, 16–29 (2015).

  133. 133.

    de Pablo, M. A. & Alvarez de Cienfuegos, G. Modulatory effects of dietary lipids on immune system functions. Immunol. Cell Biol. 78, 31–39 (2000).

  134. 134.

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

  135. 135.

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

  136. 136.

    Colonna, M. & Wang, Y. TREM2 variants: new keys to decipher Alzheimer disease pathogenesis. Nat. Rev. Neurosci. 17, 201–207 (2016).

  137. 137.

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

  138. 138.

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

  139. 139.

    Takahashi, K., Rochford, C. D. & Neumann, H. Clearance of apoptotic neurons without inflammation by microglial triggering receptor expressed on myeloid cells-2. J. Exp. Med. 201, 647–657 (2005).

  140. 140.

    Yeh, F. L., Hansen, D. V. & Sheng, M. TREM2, microglia, and neurodegenerative diseases. Trends Mol. Med. 23, 512–533 (2017).

  141. 141.

    Ulrich, J. D., Ulland, T. K., Colonna, M. & Holtzman, D. M. Elucidating the role of TREM2 in Alzheimer’s disease. Neuron 94, 237–248 (2017).

  142. 142.

    Zheng, H. et al. Opposing roles of the triggering receptor expressed on myeloid cells 2 and triggering receptor expressed on myeloid cells-like transcript 2 in microglia activation. Neurobiol. Aging 42, 132–141 (2016).

  143. 143.

    Benitez, B. A. et al. Missense variant in TREML2 protects against Alzheimer’s disease. Neurobiol. Aging 35, 1510.e19–1510.e26 (2014).

  144. 144.

    Jehle, A. W. et al. ATP-binding cassette transporter A7 enhances phagocytosis of apoptotic cells and associated ERK signaling in macrophages. J. Cell Biol. 174, 547–556 (2006).

  145. 145.

    Kim, W. S. et al. Deletion of Abca7 increases cerebral amyloid-β accumulation in the J20 mouse model of Alzheimer’s disease. J. Neurosci. 33, 4387–4394 (2013).

  146. 146.

    Sakae, N. et al. ABCA7 deficiency accelerates amyloid-β generation and Alzheimer’s neuronal pathology. J. Neurosci. 36, 3848–3859 (2016).

  147. 147.

    Crehan, H. et al. Complement receptor 1 (CR1) and Alzheimer’s disease. Immunobiology 217, 244–250 (2012).

  148. 148.

    Cunin, P. et al. Clusterin facilitates apoptotic cell clearance and prevents apoptotic cell-induced autoimmune responses. Cell Death Dis. 7, e2215 (2016).

  149. 149.

    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).

  150. 150.

    Bradshaw, E. M. et al. CD33 Alzheimer’s disease locus: altered monocyte function and amyloid biology. Nat. Neurosci. 16, 848–850 (2013).

  151. 151.

    Griciuc, A. et al. Alzheimer’s disease risk gene CD33 inhibits microglial uptake of amyloid β. Neuron 78, 631–643 (2013).

  152. 152.

    Halle, A. et al. The NALP3 inflammasome is involved in the innate immune response to amyloid-β. Nat. Immunol. 9, 857–865 (2008).

  153. 153.

    He, Y., Hara, H. & Nunez, G. Mechanism and regulation of NLRP3 inflammasome activation. Trends Biochem. Sci. 41, 1012–1021 (2016).

  154. 154.

    Walsh, J. G., Muruve, D. A. & Power, C. Inflammasomes in the CNS. Nat. Rev. Neurosci. 15, 1–14 (2014).

  155. 155.

    Jablonski, K. A. et al. Novel markers to delineate murine M1 and M2 macrophages. PLOS ONE 10, e0145342 (2015).

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Acknowledgements

This work was funded by US National Institutes of Health grants R01AG047644, R01NS090934 and R01NS034467 and support from the JPB Foundation, the Tau Consortium and the Cure Alzheimer Disease Fund to D.M.H.

Reviewer information

Nature Reviews Immunology thanks O. Butovsky and M. Heneka for their assistance with the peer review of this manuscript.

Author information

Affiliations

  1. Department of Neurology, Hope Center for Neurological Disorders, Charles F. and Joanne Knight Alzheimer’s Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA

    • Yang Shi
    •  & David M. Holtzman

Authors

  1. Search for Yang Shi in:

  2. Search for David M. Holtzman in:

Contributions

Y.S. wrote the draft of the manuscript. D.M.H. reviewed and edited the manuscript.

Competing interests

D.M.H. co-founded and is on the scientific advisory board of C2N Diagnostics. D.M.H. is on the scientific advisory board of Denali, Genentech and Proclara. D.M.H. consults for AbbVie and Eli Lilly.

Corresponding author

Correspondence to David M. Holtzman.

Glossary

Amyloid-β

A small peptide that is a major component of amyloid deposits in the brain and cerebrovasculature. It is generated from cleavage of amyloid precursor protein (APP). Depending on the carboxy-terminal cleavage site, amyloid-β peptides of varying lengths (36–43 amino acids; denoted as Aβ36–Aβ43) can be generated, among which Aβ40 and Aβ42 are the most prevalent species.

Tau

A microtubule-binding protein synthesized primarily in neurons. Under normal conditions, tau is most abundantly located in axons and serves to stabilize microtubules. In Alzheimer disease, tau becomes hyperphosphorylated, dissociates from microtubules, translocates from axons to neuronal cell bodies and dendrites and self-aggregates to form neurofibrillary tangles.

Aβ42/Aβ40 ratio

Aβ42 is more fibrillogenic than Aβ40. The level of Aβ42 produced relative to Aβ40 determines the propensity of amyloid plaque formation.

Kainic acid

A potent neuroexcitatory amino acid that serves as an agonist for kainate-class ionotropic glutamate receptors. High doses of kainic acid induce neuronal death by overexcitation of neurons.

5XFAD mice

An amyloid-β-depositing mouse model that overexpresses mutant human amyloid precursor protein (APP) carrying the Swedish (K670N and M671L), Florida (I716V) and London (V717I) mutations linked to familial Alzheimer disease along with human presenilin 1 (PS1) carrying the M146L and L286V mutations. Both transgenes are controlled under the Thy1 promoter. These mice accumulate high levels of intraneuronal Aβ42 around 6 weeks of age, followed by plaque deposition around 2 months of age.

APPSwePSEN1dE9 mice

An amyloid-β-depositing mouse model that expresses a chimeric mouse–human APP transgene carrying the Swedish mutations (K670N and M671L) and a mutant PSEN1 transgene lacking exon 9 (dE9) under the prion promoter. These mice begin to develop amyloid-β pathology around 6 months of age.

Ionized calcium-binding adaptor molecule 1

(IBA1). A microglia marker protein in the central nervous system that binds calcium and actin. It is involved in RAC GTPase-dependent membrane ruffling and phagocytosis during microglial cell activation.

3xTg-AD mice

A mouse model that harbours three mutant human genes (APPK670N,M671L, PSEN1M146V and MAPTP301L) and sequentially develops amyloid-β pathology and tau pathology starting at 6 months of age.

htau mice

A mouse model that expresses all six human tau isoforms, including 3R and 4R tau, under the endogenous human MAPT promoter and expresses no murine tau. These mice start to develop tau pathology around 9 months of age.

rTg4510 mice

A tauopathy mouse model overexpressing the 0N4R human tau isoform carrying the P301L mutation linked to familial frontotemporal dementia. Tau transgene expression is largely restricted to the forebrain by the Camk2a promoter and is regulatable by doxycycline. These mice develop tau pathology around 3–4 months of age and show substantial neuronal loss by 6 months of age.

P301S mice

A tauopathy mouse model overexpressing the 1N4R human tau isoform carrying the P301S mutation found in patients with frontotemporal dementia. These mice begin to accumulate tau pathology at 4–5 months of age and develop severe brain atrophy at 9 months of age.

APOE-targeted replacement mice

(APOE-TR mice). These mice express human apolipoprotein E (APOE) in place of the murine APOE under the endogenous murine Apoe promoter. Therefore, the expression level and pattern of human APOE are maintained in a physiological form.

APPPS1-21 mice

An amyloid-β-depositing mouse model that harbours mutant human transgenes of APP (K670N and M671L) and PSEN1 (L166P), which are both under the control of the Thy1 promoter. These mice begin to develop amyloid plaques in the neocortex at approximately 6 weeks of age, followed by deposits in the hippocampus at 3–4 months of age.

Superoxide dismutase 1 mice

(SOD1 mice). A mouse model for amyotrophic lateral sclerosis (ALS) that overexpresses human SOD1 carrying the G93A mutation. These mice recapitulate phenotypes in human patients with ALS, showing motor neuron loss in the spinal cord and paralysis in one or more limbs.

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DOI

https://doi.org/10.1038/s41577-018-0051-1