Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Neuroinflammation and microglial activation in Alzheimer disease: where do we go from here?

Nature Reviews Neurology volume 17, pages 157–172 (2021)Cite this article

Subjects

Abstract

Alzheimer disease (AD) is the most common form of neurodegenerative disease, estimated to contribute 60–70% of all cases of dementia worldwide. According to the prevailing amyloid cascade hypothesis, amyloid-β (Aβ) deposition in the brain is the initiating event in AD, although evidence is accumulating that this hypothesis is insufficient to explain many aspects of AD pathogenesis. The discovery of increased levels of inflammatory markers in patients with AD and the identification of AD risk genes associated with innate immune functions suggest that neuroinflammation has a prominent role in the pathogenesis of AD. In this Review, we discuss the interrelationships between neuroinflammation and amyloid and tau pathologies as well as the effect of neuroinflammation on the disease trajectory in AD. We specifically focus on microglia as major players in neuroinflammation and discuss the spatial and temporal variations in microglial phenotypes that are observed under different conditions. We also consider how these cells could be modulated as a therapeutic strategy for AD.

Key points

  • Neuroinflammation has demonstrated a key role in the pathogenesis of Alzheimer disease (AD), the most prevalent form of dementia.

  • Neuroinflammation encompasses a variety of inflammatory events in the CNS under pathological conditions.

  • Among the innate immune cells, microglia are the primary players in neuroinflammation.

  • Activated microglia exhibit diverse phenotypes and have multifaceted interactions with amyloid-β and tau species as well as with neuronal circuits.

  • Activated microglia might have diverse influences on the progression of AD, depending on the stage of disease, individual susceptibility and state of microglial priming.

  • Microglia could potentially be modulated at various points in the AD trajectory to either prevent or modify disease progression.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Physiological function of glial cells.
Fig. 2: Different phenotypes of microglia.
Fig. 3: Microglial response to amyloid-β species.
Fig. 4: Dynamic changes in microglial activation affect Alzheimer disease progression.

Similar content being viewed by others

References

  1. Alzheimer’s Association. 2018 Alzheimer’s disease facts and figures. Alzheimers Dement. 14, 367–429 (2018).

    Google Scholar 

  2. Kawas, C., Gray, S., Brookmeyer, R., Fozard, J. & Zonderman, A. Age-specific incidence rates of Alzheimer’s disease - the Baltimore longitudinal study of aging. Neurology 54, 2072–2077 (2000).

    CAS  PubMed  Google Scholar 

  3. McKhann, G. M. et al. The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 7, 263–269 (2011).

    PubMed  PubMed Central  Google Scholar 

  4. Braak, H. & Braak, E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 82, 239–259 (1991).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  6. Herrup, K. The case for rejecting the amyloid cascade hypothesis. Nat. Neurosci. 18, 794–799 (2015).

    CAS  PubMed  Google Scholar 

  7. Calsolaro, V. & Edison, P. Neuroinflammation in Alzheimer’s disease: current evidence and future directions. Alzheimers Dement. 12, 719–732 (2016).

    PubMed  Google Scholar 

  8. Heneka, M. T. et al. Neuroinflammation in Alzheimer’s disease. Lancet Neurol. 14, 388–405 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Obulesu, M. & Jhansilakshmi, M. Neuroinflammation in Alzheimer’s disease: an understanding of physiology and pathology. Int. J. Neurosci. 124, 227–235 (2014).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  11. Rohn, T. T. The triggering receptor expressed on myeloid cells 2: “TREM-ming” the inflammatory component associated with Alzheimer’s disease. Oxid. Med. Cell. Longev. 2013, 860959 (2013).

    PubMed  PubMed Central  Google Scholar 

  12. Thinakaran, G. & Koo, E. H. Amyloid precursor protein trafficking, processing, and function. J. Biol. Chem. 283, 29615–29619 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Selkoe, D. J. Soluble oligomers of the amyloid β-protein impair synaptic plasticity and behavior. Behav. Brain Res. 192, 106–113 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Hardy, J. & Allsop, D. Amyloid deposition as the central event in the etiology of Alzheimers-disease. Trends Pharmacol. Sci. 12, 383–388 (1991).

    CAS  PubMed  Google Scholar 

  15. Hardy, J. A. & Higgins, G. A. Alzheimer’s disease: the amyloid cascade hypothesis. Science 256, 184–185 (1992).

    CAS  PubMed  Google Scholar 

  16. Lannfelt, L., Relkin, N. R. & Siemers, E. R. Amyloid-ss-directed immunotherapy for Alzheimer’s disease. J. Intern. Med. 275, 284–295 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Small, S. A. & Duff, K. Linking Aβ and tau in late-onset Alzheimer’s disease: a dual pathway hypothesis. Neuron 60, 534–542 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Wang, Y. & Mandelkow, E. Tau in physiology and pathology. Nat. Rev. Neurosci. 17, 5–21 (2016).

    PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Bischof, G. N., Endepols, H., van Eimeren, T. & Drzezga, A. Tau-imaging in neurodegeneration. Methods 130, 114–123 (2017).

    CAS  PubMed  Google Scholar 

  21. Johnson, K. A. et al. Tau positron emission tomographic imaging in aging and early Alzheimer disease. Ann. Neurol. 79, 110–119 (2016).

    PubMed  Google Scholar 

  22. DiSabato, D. J., Quan, N. & Godbout, J. P. Neuroinflammation: the devil is in the details. J. Neurochem. 139 (Suppl. 2), 136–153 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Heneka, M. T., Kummer, M. P. & Latz, E. Innate immune activation in neurodegenerative disease. Nat. Rev. Immunol. 14, 463–477 (2014).

    CAS  PubMed  Google Scholar 

  24. Lyman, M., Lloyd, D. G., Ji, X., Vizcaychipi, M. P. & Ma, D. Neuroinflammation: the role and consequences. Neurosci. Res. 79, 1–12 (2014).

    CAS  PubMed  Google Scholar 

  25. Mishra, A., Kim, H. J., Shin, A. H. & Thayer, S. A. Synapse loss induced by interleukin-1β requires pre- and post-synaptic mechanisms. J. Neuroimmune Pharmacol. 7, 571–578 (2012).

    PubMed  PubMed Central  Google Scholar 

  26. Micheau, O. & Tschopp, J. Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes. Cell 114, 181–190 (2003).

    CAS  PubMed  Google Scholar 

  27. Hong, S. et al. Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science 352, 712–716 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Sofroniew, M. V. & Vinters, H. V. Astrocytes: biology and pathology. Acta Neuropathol. 119, 7–35 (2010).

    PubMed  Google Scholar 

  29. Attwell, D. et al. Glial and neuronal control of brain blood flow. Nature 468, 232–243 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Simard, M. & Nedergaard, M. The neurobiology of glia in the context of water and ion homeostasis. Neuroscience 129, 877–896 (2004).

    CAS  PubMed  Google Scholar 

  31. Pekny, M. et al. Astrocytes: a central element in neurological diseases. Acta Neuropathol. 131, 323–345 (2016).

    CAS  PubMed  Google Scholar 

  32. Rouach, N., Koulakoff, A., Abudara, V., Willecke, K. & Giaume, C. Astroglial metabolic networks sustain hippocampal synaptic transmission. Science 322, 1551–1555 (2008).

    CAS  PubMed  Google Scholar 

  33. Eroglu, C. & Barres, B. A. Regulation of synaptic connectivity by glia. Nature 468, 223–231 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Jessen, N. A., Munk, A. S., Lundgaard, I. & Nedergaard, M. The glymphatic system: a beginner’s guide. Neurochem. Res. 40, 2583–2599 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Tarasoff-Conway, J. M. et al. Clearance systems in the brain-implications for Alzheimer disease. Nat. Rev. Neurol. 11, 457–470 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Pekny, M., Wilhelmsson, U. & Pekna, M. The dual role of astrocyte activation and reactive gliosis. Neurosci. Lett. 565, 30–38 (2014).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

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

    PubMed  PubMed Central  Google Scholar 

  40. Khakh, B. S. & Sofroniew, M. V. Diversity of astrocyte functions and phenotypes in neural circuits. Nat. Neurosci. 18, 942–952 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Thal, D. R. et al. Amyloid β-protein (Aβ)-containing astrocytes are located preferentially near N-terminal-truncated Aβ deposits in the human entorhinal cortex. Acta Neuropathol. 100, 608–617 (2000).

    CAS  PubMed  Google Scholar 

  42. Funato, H. et al. Astrocytes containing amyloid β-protein (Aβ)-positive granules are associated with Aβ40-positive diffuse plaques in the aged human brain. Am. J. Pathol. 152, 983–992 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Wyss-Coray, T. et al. Adult mouse astrocytes degrade amyloid-β in vitro and in situ. Nat. Med. 9, 453–457 (2003).

    CAS  PubMed  Google Scholar 

  44. Jo, S. et al. GABA from reactive astrocytes impairs memory in mouse models of Alzheimer’s disease. Nat. Med. 20, 886–896 (2014).

    CAS  PubMed  Google Scholar 

  45. Chang, J. et al. NF-κB inhibits osteogenic differentiation of mesenchymal stem cells by promoting β-catenin degradation. Proc. Natl Acad. Sci. USA 110, 9469–9474 (2013).

    CAS  PubMed  Google Scholar 

  46. Winkler, E. A. et al. GLUT1 reductions exacerbate Alzheimer’s disease vasculo-neuronal dysfunction and degeneration. Nat. Neurosci. 18, 521–530 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Kisler, K., Nelson, A. R., Montagne, A. & Zlokovic, B. V. Cerebral blood flow regulation and neurovascular dysfunction in Alzheimer disease. Nat. Rev. Neurosci. 18, 419–434 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Heneka, M. T. et al. Focal glial activation coincides with increased BACE1 activation and precedes amyloid plaque deposition in APP[V717I] transgenic mice. J. Neuroinflammation 2, 22 (2005).

    PubMed  PubMed Central  Google Scholar 

  49. Harry, G. J. Microglia during development and aging. Pharmacol. Ther. 139, 313–326 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  52. Bruttger, J. et al. Genetic cell ablation reveals clusters of local self-renewing microglia in the mammalian central nervous system. Immunity 43, 92–106 (2015).

    CAS  PubMed  Google Scholar 

  53. Priller, J. et al. Targeting gene-modified hematopoietic cells to the central nervous system: use of green fluorescent protein uncovers microglial engraftment. Nat. Med. 7, 1356–1361 (2001).

    CAS  PubMed  Google Scholar 

  54. Mildner, A. et al. CCR2+Ly-6Chi monocytes are crucial for the effector phase of autoimmunity in the central nervous system. Brain 132, 2487–2500 (2009).

    PubMed  Google Scholar 

  55. Sweeney, M. D., Sagare, A. P. & Zlokovic, B. V. Blood–brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders. Nat. Rev. Neurol. 14, 133–150 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Salter, M. W. & Stevens, B. Microglia emerge as central players in brain disease. Nat. Med. 23, 1018–1027 (2017).

    CAS  PubMed  Google Scholar 

  57. Ousman, S. S. & Kubes, P. Immune surveillance in the central nervous system. Nat. Neurosci. 15, 1096–1101 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  61. Sole-Domenech, S., Cruz, D. L., Capetillo-Zarate, E. & Maxfield, F. R. The endocytic pathway in microglia during health, aging and Alzheimer’s disease. Ageing Res. Rev. 32, 89–103 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Bajetto, A., Bonavia, R., Barbero, S. & Schettini, G. Characterization of chemokines and their receptors in the central nervous system: physiopathological implications. J. Neurochem. 82, 1311–1329 (2002).

    CAS  PubMed  Google Scholar 

  63. Owens, T., Khorooshi, R., Wlodarczyk, A. & Asgari, N. Interferons in the central nervous system: a few instruments play many tunes. Glia 62, 339–355 (2014).

    PubMed  Google Scholar 

  64. Norden, D. M. & Godbout, J. P. Review: Microglia of the aged brain: primed to be activated and resistant to regulation. Neuropathol. Appl. Neurobiol. 39, 19–34 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Spittau, B. Aging microglia-phenotypes, functions and implications for age-related neurodegenerative diseases. Front. Aging Neurosci. 9 (2017).

  66. Stence, N., Waite, M. & Dailey, M. E. Dynamics of microglial activation: a confocal time-lapse analysis in hippocampal slices. Glia 33, 256–266 (2001).

    CAS  PubMed  Google Scholar 

  67. Davies, D. S., Ma, J., Jegathees, T. & Goldsbury, C. Microglia show altered morphology and reduced arborization in human brain during aging and Alzheimer’s disease. Brain Pathol. 27, 795–808 (2017).

    CAS  PubMed  Google Scholar 

  68. Rawji, K. S. et al. Immunosenescence of microglia and macrophages: impact on the ageing central nervous system. Brain 139, 653–661 (2016).

    PubMed  PubMed Central  Google Scholar 

  69. Bisht, K. et al. Dark microglia: a new phenotype predominantly associated with pathological states. Glia 64, 826–839 (2016).

    PubMed  PubMed Central  Google Scholar 

  70. Plescher, M. et al. Plaque-dependent morphological and electrophysiological heterogeneity of microglia in an Alzheimer’s disease mouse model. Glia 66, 1464–1480 (2018).

    PubMed  Google Scholar 

  71. Sanchez-Mejias, E. et al. Soluble phospho-tau from Alzheimer’s disease hippocampus drives microglial degeneration. Acta Neuropathol. 132, 897–916 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Navarro, V. et al. Microglia in Alzheimer’s disease: activated, dysfunctional or degenerative. Front. Aging Neurosci. 10, 140 (2018).

    PubMed  PubMed Central  Google Scholar 

  73. Doorn, K. J. et al. Increased amoeboid microglial density in the olfactory bulb of Parkinson’s and Alzheimer’s patients. Brain Pathol. 24, 152–165 (2014).

    CAS  PubMed  Google Scholar 

  74. Tischer, J. et al. Inhomogeneous distribution of Iba-1 characterizes microglial pathology in Alzheimer’s disease. Glia 64, 1562–1572 (2016).

    PubMed  Google Scholar 

  75. 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).

    PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  77. Nguyen, H. M. et al. Differential Kv1.3, KCa3.1, and Kir2.1 expression in “classically” and “alternatively” activated microglia. Glia 65, 106–121 (2017).

    PubMed  Google Scholar 

  78. Minett, T. et al. Microglial immunophenotype in dementia with Alzheimer’s pathology. J. Neuroinflammation 13, 135 (2016).

    PubMed  PubMed Central  Google Scholar 

  79. Hopperton, K. E., Mohammad, D., Trepanier, M. O., Giuliano, V. & Bazinet, R. P. Markers of microglia in post-mortem brain samples from patients with Alzheimer’s disease: a systematic review. Mol. Psychiatry 23, 177–198 (2018).

    CAS  PubMed  Google Scholar 

  80. Varnum, M. M. & Ikezu, T. The classification of microglial activation phenotypes on neurodegeneration and regeneration in Alzheimer’s disease brain. Arch. Immunol. Ther. Ex. 60, 251–266 (2012).

    CAS  Google Scholar 

  81. Ransohoff, R. M. A polarizing question: do M1 and M2 microglia exist? Nat. Neurosci. 19, 987–991 (2016).

    CAS  PubMed  Google Scholar 

  82. Walker, D. G. & Lue, L. F. Immune phenotypes of microglia in human neurodegenerative disease: challenges to detecting microglial polarization in human brains. Alzheimers Res. Ther. 7, 56 (2015).

    PubMed  PubMed Central  Google Scholar 

  83. Kim, C. C., Nakamura, M. C. & Hsieh, C. L. Brain trauma elicits non-canonical macrophage activation states. J. Neuroinflammation 13, 117 (2016).

    PubMed  PubMed Central  Google Scholar 

  84. Keren-Shaul, H. et al. A unique microglia type associated with restricting development of Alzheimer’s disease. Cell 169, 1276–1290.e17 (2017).

    CAS  PubMed  Google Scholar 

  85. Jay, T. R., von Saucken, V. E. & Landreth, G. E. TREM2 in neurodegenerative diseases. Mol. Neurodegeneration https://doi.org/10.1186/s13024-017-0197-5 (2017).

    Article  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  88. 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).

    CAS  PubMed  Google Scholar 

  89. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Olah, M. et al. A transcriptomic atlas of aged human microglia. Nat. Commun. https://doi.org/10.1038/s41467-018-02926-5 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  91. Tan, Y. L., Yuan, Y. & Tian, L. Microglial regional heterogeneity and its role in the brain. Mol. Psychiatry 25, 351–367 (2020).

    PubMed  Google Scholar 

  92. Masuda, T. et al. Spatial and temporal heterogeneity of mouse and human microglia at single-cell resolution. Nature 566, 388–392 (2019).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Mastroeni, D. et al. Laser-captured microglia in the Alzheimer’s and Parkinson’s brain reveal unique regional expression profiles and suggest a potential role for hepatitis B in the Alzheimer’s brain. Neurobiol. Aging 63, 12–21 (2018).

    CAS  PubMed  Google Scholar 

  95. Prokop, S. et al. Impact of TREM2 risk variants on brain region-specific immune activation and plaque microenvironment in Alzheimer’s disease patient brain samples. Acta Neuropathol. 138, 613–630 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. 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 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  99. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. 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).

    CAS  PubMed  Google Scholar 

  101. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Simon, E., Obst, J. & Gomez-Nicola, D. The evolving dialogue of microglia and neurons in Alzheimer’s disease: microglia as necessary transducers of pathology. Neuroscience 405, 24–34 (2019).

    CAS  PubMed  Google Scholar 

  103. Walker, D. G., Dalsing-Hernandez, J. E., Campbell, N. A. & Lue, L. F. Decreased expression of CD200 and CD200 receptor in Alzheimer’s disease: a potential mechanism leading to chronic inflammation. Exp. Neurol. 215, 5–19 (2009).

    CAS  PubMed  Google Scholar 

  104. 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).

    PubMed  PubMed Central  Google Scholar 

  105. Swardfager, W. et al. A meta-analysis of cytokines in Alzheimer’s disease. Biol. Psychiatry 68, 930–941 (2010).

    CAS  PubMed  Google Scholar 

  106. El Kadmiri, N., Said, N., Slassi, I., El Moutawakil, B. & Nadifi, S. Biomarkers for Alzheimer disease: classical and novel candidates’ review. Neuroscience 370, 181–190 (2018).

    CAS  PubMed  Google Scholar 

  107. Olsson, B. et al. CSF and blood biomarkers for the diagnosis of Alzheimer’s disease: a systematic review and meta-analysis. Lancet Neurol. 15, 673–684 (2016).

    CAS  PubMed  Google Scholar 

  108. Baldacci, F., Lista, S., Cavedo, E., Bonuccelli, U. & Hampel, H. Diagnostic function of the neuroinflammatory biomarker YKL-40 in Alzheimer’s disease and other neurodegenerative diseases. Expert Rev. Proteom. 14, 285–299 (2017).

    CAS  Google Scholar 

  109. Sutphen, C. L. et al. Longitudinal cerebrospinal fluid biomarker changes in preclinical Alzheimer disease during middle age. JAMA Neurol. 72, 1029–1042 (2015).

    PubMed  PubMed Central  Google Scholar 

  110. Alcolea, D. et al. Amyloid precursor protein metabolism and inflammation markers in preclinical Alzheimer disease. Neurology 85, 626–633 (2015).

    CAS  PubMed  Google Scholar 

  111. Edison, P. & Brooks, D. J. Role of neuroinflammation in the trajectory of Alzheimer’s disease and in vivo quantification using PET. J. Alzheimers Dis. 64, S339–S351 (2018).

    PubMed  Google Scholar 

  112. Venneti, S., Lopresti, B. J. & Wiley, C. A. The peripheral benzodiazepine receptor (Translocator protein 18 kDa) in microglia: from pathology to imaging. Prog. Neurobiol. 80, 308–322 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Diorio, D., Welner, S. A., Butterworth, R. F., Meaney, M. J. & Suranyi-Cadotte, B. E. Peripheral benzodiazepine binding sites in Alzheimer’s disease frontal and temporal cortex. Neurobiol. Aging 12, 255–258 (1991).

    CAS  PubMed  Google Scholar 

  114. Junck, L. et al. PET imaging of human gliomas with ligands for the peripheral benzodiazepine binding-site. Ann. Neurol. 26, 752–758 (1989).

    CAS  PubMed  Google Scholar 

  115. Alam, M. M., Lee, J. & Lee, S. Y. Recent progress in the development of TSPO PET Ligands for neuroinflammation imaging in neurological diseases. Nucl. Med. Mol. Imaging 51, 283–296 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Owen, D. R. J. et al. Mixed-affinity binding in humans with 18-kDa translocator protein ligands. J. Nucl. Med. 52, 24–32 (2011).

    CAS  PubMed  Google Scholar 

  117. Kreisl, W. C. et al. A genetic polymorphism for translocator protein 18 kDa affects both in vitro and in vivo radioligand binding in human brain to this putative biomarker of neuroinflammation. J. Cereb. Blood Flow. Metab. 33, 53–58 (2013).

    CAS  PubMed  Google Scholar 

  118. Fan, Z. et al. Can studies of neuroinflammation in a TSPO genetic subgroup (HAB or MAB) be applied to the entire AD cohort? J. Nucl. Med. 56, 707–713 (2015).

    CAS  PubMed  Google Scholar 

  119. Lavisse, S. et al. Reactive astrocytes overexpress TSPO and are detected by TSPO positron emission tomography imaging. J. Neurosci. 32, 10809–10818 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Ji, B. et al. Imaging of peripheral benzodiazepine receptor expression as biomarkers of detrimental versus beneficial glial responses in mouse models of Alzheimer’s and other CNS pathologies. J. Neurosci. 28, 12255–12267 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Rojas, S. et al. Imaging brain inflammation with [11C]PK11195 by PET and induction of the peripheral-type benzodiazepine receptor after transient focal ischemia in rats. J. Cereb. Blood Flow. Metab. 27, 1975–1986 (2007).

    CAS  PubMed  Google Scholar 

  122. Venneti, S., Wang, G., Nguyen, J. & Wiley, C. A. The positron emission tomography ligand DAA1106 binds with high affinity to activated microglia in human neurological disorders. J. Neuropathol. Exp. Neurol. 67, 1001–1010 (2008).

    PubMed  PubMed Central  Google Scholar 

  123. Janssen, B., Vugts, D. J., Windhorst, A. D. & Mach, R. H. PET imaging of microglial activation-beyond targeting TSPO. Molecules https://doi.org/10.3390/molecules23030607 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  124. Narayanaswami, V. et al. Emerging PET radiotracers and targets for imaging of neuroinflammation in neurodegenerative diseases: outlook beyond TSPO. Mol. Imaging 17, 1536012118792317 (2018).

    PubMed  PubMed Central  Google Scholar 

  125. Beaino, W. et al. Purinergic receptors P2Y12R and P2X7R: potential targets for PET imaging of microglia phenotypes in multiple sclerosis. J. Neuroinflammation 14, 259 (2017).

    PubMed  PubMed Central  Google Scholar 

  126. Mcgeer, P. L., Itagaki, S., Tago, H. & Mcgeer, E. G. Reactive microglia in patients with senile dementia of Alzheimer type are positive for the histocompatibility glycoprotein HLA-DR. Neurosci. Lett. 79, 195–200 (1987).

    CAS  PubMed  Google Scholar 

  127. Tooyama, I., Kimura, H., Akiyama, H. & Mcgeer, P. L. Reactive microglia express class-I and class-II major histocompatibility complex antigens in Alzheimers disease. Brain Res. 523, 273–280 (1990).

    CAS  PubMed  Google Scholar 

  128. Hayes, A., Thaker, U., Iwatsubo, T., Pickering-Brown, S. M. & Mann, D. M. Pathological relationships between microglial cell activity and tau and amyloid β protein in patients with Alzheimer’s disease. Neurosci. Lett. 331, 171–174 (2002).

    CAS  PubMed  Google Scholar 

  129. Dani, M. et al. Microglial activation correlates in vivo with both tau and amyloid in Alzheimer’s disease. Brain 141, 2740–2754 (2018).

    PubMed  Google Scholar 

  130. Kitazawa, M., Yamasaki, T. R. & LaFerla, F. M. Microglia as a potential bridge between the amyloid β-peptide and tau. Ann. N.Y. Acad. Sci. 1035, 85–103 (2004).

    CAS  PubMed  Google Scholar 

  131. McGeer, P. L. & McGeer, E. G. The amyloid cascade-inflammatory hypothesis of Alzheimer disease: implications for therapy. Acta Neuropathol. 126, 479–497 (2013).

    CAS  PubMed  Google Scholar 

  132. Delbo, R., Angeretti, N., Lucca, E., Desimoni, M. G. & Forloni, G. Reciprocal control of inflammatory cytokines, IL-1 and IL-6, and β-amyloid production in cultures. Neurosci. Lett. 188, 70–74 (1995).

    CAS  Google Scholar 

  133. Akiyama, H. et al. Inflammation and Alzheimer’s disease. Neurobiol. Aging 21, 383–421 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Hanisch, U. K. Microglia as a source and target of cytokines. Glia 40, 140–155 (2002).

    PubMed  Google Scholar 

  135. Yang, T., Li, S. M., Xu, H. X., Walsh, D. M. & Selkoe, D. J. Large soluble oligomers of amyloid β-protein from Alzheimer brain are far less neuroactive than the smaller oligomers to which they dissociate. J. Neurosci. 37, 152–163 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Venegas, C. & Heneka, M. T. Danger-associated molecular patterns in Alzheimer’s disease. J. Leukoc. Biol. 101, 87–98 (2017).

    CAS  PubMed  Google Scholar 

  137. Liu, S. et al. TLR2 is a primary receptor for Alzheimer’s amyloid β peptide to trigger neuroinflammatory activation. J. Immunol. 188, 1098–1107 (2012).

    CAS  PubMed  Google Scholar 

  138. Murgas, P., Godoy, B. & von Bernhardi, R. Aβ potentiates inflammatory activation of glial cells induced by scavenger receptor ligands and inflammatory mediators in culture. Neurotox. Res. 22, 69–78 (2012).

    CAS  PubMed  Google Scholar 

  139. Alawieyah Syed Mortadza, S., Sim, J. A., Neubrand, V. E. & Jiang, L. H. A critical role of TRPM2 channel in Aβ42-induced microglial activation and generation of tumor necrosis factor-α. Glia 66, 562–575 (2018).

    PubMed  Google Scholar 

  140. Husemann, J., Loike, J. D., Kodama, T. & Silverstein, S. C. Scavenger receptor class B type I (SR-BI) mediates adhesion of neonatal murine microglia to fibrillar β-amyloid. J. Neuroimmunol. 114, 142–150 (2001).

    CAS  PubMed  Google Scholar 

  141. Koenigsknecht, J. & Landreth, G. Microglial phagocytosis of fibrillar β-amyloid through a β1 integrin-dependent mechanism. J. Neurosci. 24, 9838–9846 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. Malko, P., Syed Mortadza, S. A., McWilliam, J. & Jiang, L.-H. TRPM2 channel in microglia as a new player in neuroinflammation associated with a spectrum of central nervous system pathologies. Front. Pharmacol. 10, 239 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Strowig, T., Henao-Mejia, J., Elinav, E. & Flavell, R. Inflammasomes in health and disease. Nature 481, 278–286 (2012).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  145. White, C. S., Lawrence, C. B., Brough, D. & Rivers-Auty, J. Inflammasomes as therapeutic targets for Alzheimer’s disease. Brain Pathol. 27, 223–234 (2017).

    PubMed  Google Scholar 

  146. Doens, D. & Fernandez, P. L. Microglia receptors and their implications in the response to amyloid-β for Alzheimer’s disease pathogenesis. J. Neuroinflammation 11, 48 (2014).

    PubMed  PubMed Central  Google Scholar 

  147. Guerreiro, R. & Hardy, J. Genetics of Alzheimer’s disease. Neurotherapeutics 11, 732–737 (2014).

    PubMed  PubMed Central  Google Scholar 

  148. Ulland, T. K. et al. TREM2 maintains microglial metabolic fitness in Alzheimer’s disease. Cell 170, 649–663.e13 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Paresce, D. M., Chung, H. Y. & Maxfield, F. R. Slow degradation of aggregates of the Alzheimer’s disease amyloid β-protein by microglial cells. J. Biol. Chem. 272, 29390–29397 (1997).

    CAS  PubMed  Google Scholar 

  150. Cho, M. H. et al. Autophagy in microglia degrades extracellular β-amyloid fibrils and regulates the NLRP3 inflammasome. Autophagy 10, 1761–1775 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  151. Plaza-Zabala, A., Sierra-Torre, V. & Sierra, A. Autophagy and microglia: novel partners in neurodegeneration and aging. Int. J. Mol. Sci. 18, 598 (2017).

    PubMed Central  Google Scholar 

  152. Pan, X.-D. et al. Microglial phagocytosis induced by fibrillar β-amyloid is attenuated by oligomeric β-amyloid: implications for Alzheimer’s disease. Mol. Neurodegener. 6, 45 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. Hellwig, S. et al. Forebrain microglia from wild-type but not adult 5xFAD mice prevent amyloid-β plaque formation in organotypic hippocampal slice cultures. Sci. Rep. 5, 14624 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  154. Spangenberg, E. E. & Green, K. N. Inflammation in Alzheimer’s disease: lessons learned from microglia-depletion models. Brain Behav. Immun. 61, 1–11 (2017).

    CAS  PubMed  Google Scholar 

  155. Raha-Chowdhury, R. et al. Erythromyeloid-derived TREM2: a major determinant of Alzheimer’s disease pathology in Down syndrome. J. Alzheimers Dis. 61, 1143–1162 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  156. Streit, W. J., Sammons, N. W., Kuhns, A. J. & Sparks, D. L. Dystrophic microglia in the aging human brain. Glia 45, 208–212 (2004).

    PubMed  Google Scholar 

  157. Streit, W. J. Microglial senescence: does the brain’s immune system have an expiration date? Trends Neurosci. 29, 506–510 (2006).

    CAS  PubMed  Google Scholar 

  158. Hawcroft, G., Gardner, S. H. & Hull, M. A. Activation of peroxisome proliferator-activated receptor gamma does not explain the antiproliferative activity of the nonsteroidal anti-inflammatory drug indomethacin on human colorectal cancer cells. J. Pharmacol. Exp. Ther. 305, 632–637 (2003).

    CAS  PubMed  Google Scholar 

  159. Chen, C. H. et al. Increased NF-κB signalling up-regulates BACE1 expression and its therapeutic potential in Alzheimer’s disease. Int. J. Neuropsychopharmacol. 15, 77–90 (2012).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  161. Morales, I., Jimenez, J. M., Mancilla, M. & Maccioni, R. B. Tau oligomers and fibrils induce activation of microglial cells. J. Alzheimers Dis. 37, 849–856 (2013).

    CAS  PubMed  Google Scholar 

  162. Wes, P. D. et al. Tau overexpression impacts a neuroinflammation gene expression network perturbed in Alzheimer’s disease. PLoS ONE 9, e106050 (2014).

    PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  164. Streit, W. J. et al. Microglial activation occurs late during preclinical Alzheimer’s disease. Glia 66, 2550–2562 (2018).

    PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  166. Felsky, D. et al. Neuropathological correlates and genetic architecture of microglial activation in elderly human brain. Nat. Commun. 10, 409 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  167. Ising, C. et al. NLRP3 inflammasome activation drives tau pathology. Nature 575, 669–673 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  168. Chen, W. et al. Increased tauopathy drives microglia-mediated clearance of β-amyloid. Acta Neuropathol. Commun. 4, 63 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  169. Sekiya, M. et al. Integrated biology approach reveals molecular and pathological interactions among Alzheimer’s Aβ42, Tau, TREM2, and TYROBP in Drosophila models. Genome Med. https://doi.org/10.1186/s13073-018-0530-9 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  170. Takahashi, H. et al. Opposing effects of progranulin deficiency on amyloid and tau pathologies via microglial TYROBP network. Acta Neuropathol. 133, 785–807 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  171. Lee, S. et al. Opposing effects of membrane-anchored CX3CL1 on amyloid and tau pathologies via the p38 MAPK pathway. J. Neurosci. 34, 12538–12546 (2014).

    PubMed  PubMed Central  Google Scholar 

  172. Bolos, M. et al. Absence of CX3CR1 impairs the internalization of tau by microglia. Mol. Neurodegeneration https://doi.org/10.1186/s13024-017-0200-1 (2017).

    Article  Google Scholar 

  173. Hamelin, L. et al. Early and protective microglial activation in Alzheimer’s disease: a prospective study using 18F-DPA-714 PET imaging. Brain 139, 1252–1264 (2016).

    PubMed  Google Scholar 

  174. Fan, Z., Brooks, D. J., Okello, A. & Edison, P. An early and late peak in microglial activation in Alzheimer’s disease trajectory. Brain 140, 792–803 (2017).

    PubMed  PubMed Central  Google Scholar 

  175. Parbo, P. et al. Does inflammation precede tau aggregation in early Alzheimer’s disease? A PET study. Neurobiol. Dis. 117, 211–216 (2018).

    CAS  PubMed  Google Scholar 

  176. Dunn, N., Mullee, M., Perry, V. H. & Holmes, C. Association between dementia and infectious disease — evidence from a case-control study. Alzheimers Dis. Assoc. Disord. 19, 91–94 (2005).

    Google Scholar 

  177. t’ Veld, B. A. et al. Nonsteroidal antiinflammatory drugs and the risk of Alzheimer’s disease. N. Engl. J. Med. 345, 1515–1521 (2001).

    Google Scholar 

  178. Etminan, M., Gill, S. & Samii, A. Effect of non-steroidal anti-inflammatory drugs on risk of Alzheimer’s disease: systematic review and meta-analysis of observational studies. Brit. Med. J. 327, 128 (2003).

    CAS  PubMed  Google Scholar 

  179. Johnson, V. E. et al. Inflammation and white matter degeneration persist for years after a single traumatic brain injury. Brain 136, 28–42 (2013).

    PubMed  PubMed Central  Google Scholar 

  180. Hanzel, C. E. et al. Neuronal driven pre-plaque inflammation in a transgenic rat model of Alzheimer’s disease. Neurobiol. Aging 35, 2249–2262 (2014).

    CAS  PubMed  Google Scholar 

  181. Okello, A. et al. Microglial activation and amyloid deposition in mild cognitive impairment. A PET study. Neurology 72, 56–62 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  182. Femminella, G. D. et al. Microglial activation in early Alzheimer trajectory is associated with higher gray matter volume. Neurology 92, e1331–e1343 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  183. Dani, M. et al. Tau aggregation correlates with amyloid deposition in both mild cognitive impairment and Alzheimer’s disease subjects. J. Alzheimers Dis. 70, 455–465 (2019).

    PubMed  Google Scholar 

  184. Hamelin, L. et al. Early and protective microglial activation in Alzheimer’s disease: a prospective study using 18F-DPA-714 PET imaging. Brain 139, 1252–1264 (2016).

    PubMed  Google Scholar 

  185. Kreisl, W. C., Henter, I. D. & Innis, R. B. Imaging translocator protein as a biomarker of neuroinflammation in dementia. Adv. Pharmacol. 82, 163–185 (2018).

    CAS  PubMed  Google Scholar 

  186. Kreisl, W. C. et al. 11C-PBR28 binding to translocator protein increases with progression of Alzheimer’s disease. Neurobiol. Aging 44, 53–61 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  187. Philippens, I. H. et al. Acceleration of amyloidosis by inflammation in the amyloid-β marmoset monkey model of Alzheimer’s disease. J. Alzheimers Dis. 55, 101–113 (2017).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  189. Lambert, J. C. et al. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease. Nat. Genet. 45, 1452–U1206 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  190. Perry, V. H. & Holmes, C. Microglial priming in neurodegenerative disease. Nat. Rev. Neurol. 10, 217–224 (2014).

    CAS  PubMed  Google Scholar 

  191. Femminella, G. D. et al. Does microglial activation influence hippocampal volume and neuronal function in Alzheimer’s disease and Parkinson’s disease dementia? J. Alzheimers Dis. 51, 1275–1289 (2016).

    CAS  PubMed  Google Scholar 

  192. Fan, Z. et al. Influence of microglial activation on neuronal function in Alzheimer’s and Parkinson’s disease dementia. Alzheimers Dement. 11, 608–621.e7 (2015).

    PubMed  Google Scholar 

  193. Yokoi, T. et al. Involvement of the precuneus/posterior cingulate cortex is significant for the development of Alzheimer’s disease: a PET (THK5351, PiB) and resting fMRI study. Front. Aging Neurosci. 10, 304 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  194. Passamonti, L. et al. Neuroinflammation and functional connectivity in Alzheimer’s disease: interactive influences on cognitive performance. J. Neurosci. 39, 7218–7226 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  195. Melah, K. E. et al. Cerebrospinal fluid markers of Alzheimer’s disease pathology and microglial activation are associated with altered white matter microstructure in asymptomatic adults at risk for Alzheimer’s disease. J. Alzheimers Dis. 50, 873–886 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  196. Edison, P. et al. Microglia, amyloid, and cognition in Alzheimer’s disease: an [11C](R)PK11195-PET and [11C]PIB-PET study. Neurobiol. Dis. 32, 412–419 (2008).

    CAS  PubMed  Google Scholar 

  197. Yokokura, M. et al. In vivo changes in microglial activation and amyloid deposits in brain regions with hypometabolism in Alzheimer’s disease. Eur. J. Nucl. Med. Mol. Imaging 38, 343–351 (2011).

    CAS  PubMed  Google Scholar 

  198. Kreisl, W. C. et al. In vivo radioligand binding to translocator protein correlates with severity of Alzheimer’s disease. Brain 136, 2228–2238 (2013).

    PubMed  PubMed Central  Google Scholar 

  199. Combs, C. K., Karlo, J. C., Kao, S. C. & Landreth, G. E. β-Amyloid stimulation of microglia and monocytes results in TNFα-dependent expression of inducible nitric oxide synthase and neuronal apoptosis. J. Neurosci. 21, 1179–1188 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  200. Floden, A. M., Li, S. & Combs, C. K. β-amyloid-stimulated microglia induce neuron death via synergistic stimulation of tumor necrosis factor α and NMDA receptors. J. Neurosci. 25, 2566–2575 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  201. Martin, E., Boucher, C., Fontaine, B. & Delarasse, C. Distinct inflammatory phenotypes of microglia and monocyte-derived macrophages in Alzheimer’s disease models: effects of aging and amyloid pathology. Aging Cell 16, 27–38 (2017).

    CAS  PubMed  Google Scholar 

  202. Neniskyte, U., Neher, J. J. & Brown, G. C. Neuronal death induced by nanomolar amyloid β is mediated by primary phagocytosis of neurons by microglia. J. Biol. Chem. 286, 39904–39913 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  203. Shi, Q. Q. et al. Complement C3 deficiency protects against neurodegeneration in aged plaque-rich APP/PS1 mice. Sci. Transl. Med. https://doi.org/10.1126/scitranslmed.aaf6295 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  204. Serrano-Pozo, A., Betensky, R. A., Frosch, M. P. & Hyman, B. T. Plaque-associated local toxicity increases over the clinical course of Alzheimer disease. Am. J. Pathol. 186, 375–384 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  205. Raj, A., Kuceyeski, A. & Weiner, M. A network diffusion model of disease progression in dementia. Neuron 73, 1204–1215 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  206. Braak, H. & Del Tredici, K. The preclinical phase of the pathological process underlying sporadic Alzheimer’s disease. Brain 138, 2814–2833 (2015).

    PubMed  Google Scholar 

  207. Fan, Z., Okello, A. A., Brooks, D. J. & Edison, P. Longitudinal influence of microglial activation and amyloid on neuronal function in Alzheimer’s disease. Brain 138, 3685–3698 (2015).

    PubMed  Google Scholar 

  208. Hamelin, L. et al. Distinct dynamic profiles of microglial activation are associated with progression of Alzheimer’s disease. Brain 141, 1855–1870 (2018).

    PubMed  Google Scholar 

  209. Cagnin, A. et al. In-vivo measurement of activated microglia in dementia. Lancet 358, 461–467 (2001).

    CAS  PubMed  Google Scholar 

  210. Wiley, C. A. et al. Carbon 11-labeled Pittsburgh compound B and carbon 11-labeled (R)-PK11195 positron emission tomographic imaging in Alzheimer disease. Arch. Neurol. 66, 60–67 (2009).

    PubMed  PubMed Central  Google Scholar 

  211. Lopez-Picon, F. R. et al. Neuroinflammation appears early on PET imaging and then plateaus in a mouse model of Alzheimer disease. J. Nucl. Med. 59, 509–515 (2018).

    CAS  PubMed  Google Scholar 

  212. Yokokura, M. et al. Depiction of microglial activation in aging and dementia: positron emission tomography with [11C]DPA713 versus [11C](R)PK11195. J. Cereb. Blood Flow Metab. 37, 877–889 (2017).

    CAS  PubMed  Google Scholar 

  213. Lyoo, C. H. et al. Cerebellum can serve as a pseudo-reference region in Alzheimer disease to detect neuroinflammation measured with PET radioligand binding to translocator protein. J. Nucl. Med. 56, 701–706 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  214. Yaqub, M. et al. Optimization of supervised cluster analysis for extracting reference tissue input curves in (R)-[11C]PK11195 brain PET studies. J. Cereb. Blood Flow Metab. 32, 1600–1608 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  215. Bradburn, S., Murgatroyd, C. & Ray, N. Neuroinflammation in mild cognitive impairment and Alzheimer’s disease: a meta-analysis. Ageing Res. Rev. 50, 1–8 (2019).

    CAS  PubMed  Google Scholar 

  216. Miguel-Alvarez, M. et al. Non-steroidal anti-inflammatory drugs as a treatment for Alzheimer’s disease: a systematic review and meta-analysis of treatment effect. Drugs Aging 32, 139–147 (2015).

    CAS  PubMed  Google Scholar 

  217. Elewa, H. F., Hilali, H., Hess, D. C., Machado, L. S. & Fagan, S. C. Minocycline for short-term neuroprotection. Pharmacotherapy 26, 515–521 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  218. Garcez, M. L. et al. Minocycline reduces inflammatory parameters in the brain structures and serum and reverses memory impairment caused by the administration of amyloid β (1-42) in mice. Prog. Neuropsychopharmacol. Biol. Psychiatry 77, 23–31 (2017).

    CAS  PubMed  Google Scholar 

  219. Howard, R. et al. Minocycline at 2 different dosages vs placebo for patients with mild Alzheimer disease: a randomized clinical trial. JAMA Neurol. 77, 164–174 (2020).

    PubMed  Google Scholar 

  220. Munoz, L. & Ammit, A. J. Targeting p38 MAPK pathway for the treatment of Alzheimer’s disease. Neuropharmacology 58, 561–568 (2010).

    CAS  PubMed  Google Scholar 

  221. Thawkar, B. S. & Kaur, G. Inhibitors of NF-κB and P2X7/NLRP3/caspase 1 pathway in microglia: novel therapeutic opportunities in neuroinflammation induced early-stage Alzheimer’s disease. J. Neuroimmunol. 326, 62–74 (2019).

    CAS  PubMed  Google Scholar 

  222. Mandrekar-Colucci, S., Karlo, J. C. & Landreth, G. E. Mechanisms underlying the rapid peroxisome proliferator-activated receptor-gamma-mediated amyloid clearance and reversal of cognitive deficits in a murine model of Alzheimer’s disease. J. Neurosci. 32, 10117–10128 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  223. Flores, J. et al. Caspase-1 inhibition alleviates cognitive impairment and neuropathology in an Alzheimer’s disease mouse model. Nat. Commun. 9, 3916 (2018).

    PubMed  PubMed Central  Google Scholar 

  224. Steeland, S. et al. Counteracting the effects of TNF receptor-1 has therapeutic potential in Alzheimer’s disease. EMBO Mol. Med. 10, e8300 (2018).

    PubMed  PubMed Central  Google Scholar 

  225. Shi, J. Q. et al. Anti-TNF-α reduces amyloid plaques and tau phosphorylation and induces CD11c-positive dendritic-like cell in the APP/PS1 transgenic mouse brains. Brain Res. 1368, 239–247 (2011).

    CAS  PubMed  Google Scholar 

  226. Tobinick, E. L. & Gross, H. Rapid improvement in verbal fluency and aphasia following perispinal etanercept in Alzheimer’s disease. BMC Neurol. 8, 27 (2008).

    PubMed  PubMed Central  Google Scholar 

  227. Butchart, J. et al. Etanercept in Alzheimer disease: a randomized, placebo-controlled, double-blind, phase 2 trial. Neurology 84, 2161–2168 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  228. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  229. Grimaldi, L. M. et al. A pilot study on the use of interferon β1a in early Alzheimer’s disease subjects. J. Neuroinflammation 11, 30 (2014).

    PubMed  PubMed Central  Google Scholar 

  230. Moussa, C. et al. Resveratrol regulates neuro-inflammation and induces adaptive immunity in Alzheimer’s disease. J. Neuroinflammation 14, 1 (2017).

    PubMed  PubMed Central  Google Scholar 

  231. Alves, S. et al. Interleukin-2 improves amyloid pathology, synaptic failure and memory in Alzheimer’s disease mice. Brain 140, 826–842 (2017).

    PubMed  Google Scholar 

  232. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  233. Fu, A. K. et al. IL-33 ameliorates Alzheimer’s disease-like pathology and cognitive decline. Proc. Natl Acad. Sci. USA 113, E2705–E2713 (2016).

    CAS  PubMed  Google Scholar 

  234. Zheng, C., Zhou, X. W. & Wang, J. Z. The dual roles of cytokines in Alzheimer’s disease: update on interleukins, TNF-α, TGF-β and IFN-γ. Transl. Neurodegener. 5, 7 (2016).

    PubMed  PubMed Central  Google Scholar 

  235. Mandrekar-Colucci, S. & Landreth, G. E. Nuclear receptors as therapeutic targets for Alzheimer’s disease. Expert Opin. Ther. Targets 15, 1085–1097 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  236. Escribano, L. et al. Rosiglitazone rescues memory impairment in Alzheimer’s transgenic mice: mechanisms involving a reduced amyloid and tau pathology. Neuropsychopharmacology 35, 1593–1604 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  237. Yamanaka, M. et al. PPARγ/RXRα-induced and CD36-mediated microglial amyloid-β phagocytosis results in cognitive improvement in amyloid precursor protein/presenilin 1 mice. J. Neurosci. 32, 17321–17331 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  238. Gold, M. et al. Rosiglitazone monotherapy in mild-to-moderate Alzheimer’s disease: results from a randomized, double-blind, placebo-controlled phase III study. Dement. Geriatr. Cogn. Disord. 30, 131–146 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  239. Yin, J. et al. NLRP3 inflammasome inhibitor ameliorates amyloid pathology in a mouse model of Alzheimer’s disease. Mol. Neurobiol. 55, 1977–1987 (2018).

    CAS  PubMed  Google Scholar 

  240. Perry, V. H. & Teeling, J. Microglia and macrophages of the central nervous system: the contribution of microglia priming and systemic inflammation to chronic neurodegeneration. Semin. Immunopathol. 35, 601–612 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  241. Dias, H. K., Brown, C. L., Polidori, M. C., Lip, G. Y. & Griffiths, H. R. LDL-lipids from patients with hypercholesterolaemia and Alzheimer’s disease are inflammatory to microvascular endothelial cells: mitigation by statin intervention. Clin. Sci. 129, 1195–1206 (2015).

    CAS  PubMed Central  Google Scholar 

  242. Verdile, G. et al. Inflammation and oxidative stress: the molecular connectivity between insulin resistance, obesity, and Alzheimer’s disease. Mediators Inflamm. 2015, 105828 (2015).

    PubMed  PubMed Central  Google Scholar 

  243. Chen, H. et al. Folic acid supplementation mitigates Alzheimer’s disease by reducing inflammation: a randomized controlled trial. Mediators Inflamm. 2016, 5912146 (2016).

    PubMed  PubMed Central  Google Scholar 

  244. Vedin, I. et al. Effects of docosahexaenoic acid-rich σ-3 fatty acid supplementation on cytokine release from blood mononuclear leukocytes: the OmegAD study. Am. J. Clin. Nutr. 87, 1616–1622 (2008).

    CAS  PubMed  Google Scholar 

  245. Andrieu, S. et al. Effect of long-term omega 3 polyunsaturated fatty acid supplementation with or without multidomain intervention on cognitive function in elderly adults with memory complaints (MAPT): a randomised, placebo-controlled trial. Lancet Neurol. 16, 377–389 (2017).

    CAS  PubMed  Google Scholar 

  246. Ngandu, T. et al. A 2 year multidomain intervention of diet, exercise, cognitive training, and vascular risk monitoring versus control to prevent cognitive decline in at-risk elderly people (FINGER): a randomised controlled trial. Lancet 385, 2255–2263 (2015).

    PubMed  Google Scholar 

  247. Kim, S. et al. Protocol for a pragmatic randomised controlled trial of body brain life-general practice and a lifestyle modification programme to decrease dementia risk exposure in a primary care setting. BMJ Open 8, e019329 (2018).

    PubMed  PubMed Central  Google Scholar 

  248. Rosenberg, A., Mangialasche, F., Ngandu, T., Solomon, A. & Kivipelto, M. Multidomain interventions to prevent cognitive impairment, Alzheimer’s disease, and dementia: from FINGER to World-Wide FINGERS. J. Prev. Alzheimers Dis. 7, 29–36 (2020).

    CAS  PubMed  Google Scholar 

  249. Jack, C. R. et al. Tracking pathophysiological processes in Alzheimer’s disease: an updated hypothetical model of dynamic biomarkers. Lancet Neurol. 12, 207–216 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

F.L. is sponsored by the China Scholarship Council to undertake postgraduate research.

Author information

Authors and Affiliations

  1. Department of Brain Sciences, Imperial College London, Hammersmith Hospital Campus, London, UK

    Fangda Leng & Paul Edison

Authors
  1. Fangda Leng
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Paul Edison
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

F.L. contributed to writing of the manuscript. P.E. made substantial contributions to discussions of the content and revision of the manuscript. Both authors researched data for the manuscript.

Corresponding author

Correspondence to Paul Edison.

Ethics declarations

Competing interests

P.E. declares that he was formerly funded by the Medical Research Council and now by the Higher Education Funding Council for England (HEFCE), that he has received grants from Alzheimer’s Drug Discovery Foundation, Alzheimer’s Research UK, Alzheimer’s Society UK, GE Healthcare, Novo Nordisk and Piramal Life Sciences, and that he has acted as a consultant to Novo Nordisk and Pfizer. The other authors declare no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Leng, F., Edison, P. Neuroinflammation and microglial activation in Alzheimer disease: where do we go from here?. Nat Rev Neurol 17, 157–172 (2021). https://doi.org/10.1038/s41582-020-00435-y

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41582-020-00435-y

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing