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.

Microglial priming in neurodegenerative disease

Key Points

  • Microglia are involved in the communication of systemic inflammation to the brain

  • Microglia become primed by systemic inflammation or neurodegeneration

  • The exaggerated response of primed microglia to systemic inflammation contributes to the pathogenesis of neurodegenerative disease

  • Modulation of systemic inflammation offers novel strategies in the prevention and therapy of neurodegenerative disease

Abstract

Under physiological conditions, the number and function of microglia—the resident macrophages of the CNS—is tightly controlled by the local microenvironment. In response to neurodegeneration and the accumulation of abnormally folded proteins, however, microglia multiply and adopt an activated state—a process referred to as priming. Studies using preclinical animal models have shown that priming of microglia is driven by changes in their microenvironment and the release of molecules that drive their proliferation. Priming makes the microglia susceptible to a secondary inflammatory stimulus, which can then trigger an exaggerated inflammatory response. The secondary stimulus can arise within the CNS, but in elderly individuals, the secondary stimulus most commonly arises from a systemic disease with an inflammatory component. The concept of microglial priming, and the subsequent exaggerated response of these cells to secondary systemic inflammation, opens the way to treat neurodegenerative diseases by targeting systemic disease or interrupting the signalling pathways that mediate the CNS response to systemic inflammation. Both lifestyle changes and pharmacological therapies could, therefore, provide efficient means to slow down or halt neurodegeneration.

Your institute does not have access to this article

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Effects of systemic inflammation on microglia.

References

  1. de Haas, A. H., Boddeke, H. W. & Biber, K. Region-specific expression of immunoregulatory proteins on microglia in the healthy CNS. Glia 56, 888–894 (2008).

    PubMed  Google Scholar 

  2. Ransohoff, R. M. & Perry, V. H. Microglial physiology: unique stimuli, specialized responses. Annu. Rev. Immunol. 27, 119–145 (2009).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  4. 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 

  5. Wake, H., Moorhouse, A. J., Jinno, S., Kohsaka, S. & Nabekura, J. Resting microglia directly monitor the functional state of synapses in vivo and determine the fate of ischemic terminals. J. Neurosci. 29, 3974–3980 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Tremblay, M. È., Lowery, R. L. & Majewska, A. K. Microglial interactions with synapses are modulated by visual experience. PLoS Biol. 8, e1000527 (2010).

    PubMed  PubMed Central  Google Scholar 

  7. Sogn, C. J., Puchades, M. & Gundersen, V. Rare contacts between synapses and microglial processes containing high levels of Iba1 and actin—a postembedding immunogold study in the healthy rat brain. Eur. J. Neurosci. 38, 2030–2040 (2013).

    PubMed  Google Scholar 

  8. Dantzer, R., O'Connor, J. C., Freund, G. G., Johnson, R. W. & Kelley, K. W. From inflammation to sickness and depression: when the immune system subjugates the brain. Nat. Rev. Neurosci. 9, 46–56 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Andersson, U. & Tracey, K. J. Reflex principles of immunological homeostasis. Annu. Rev. Immunol. 30, 313–335 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Perry, V. H. The influence of systemic inflammation on inflammation in the brain: implications for chronic neurodegenerative disease. Brain Behav. Immun. 18, 407–413 (2004).

    CAS  PubMed  Google Scholar 

  11. Perry, V. H., Cunningham, C. & Holmes, C. Systemic infections and inflammation affect chronic neurodegeneration. Nat. Rev. Immunol. 7, 161–167 (2007).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Colton, C. A., Mott, R. T., Sharpe, H., Xu, Q. & Van Nostrand, W. E. Expression profiles for macrophage alternative activation genes in AD and in mouse models of AD. J. Neuroinflammation 3, 27 (2006).

    PubMed  PubMed Central  Google Scholar 

  14. Perry, V. H. Contribution of systemic inflammation to chronic neurodegeneration. Acta Neuropathol. 120, 277–286 (2010).

    CAS  PubMed  Google Scholar 

  15. Scheffel, J. et al. Toll-like receptor activation reveals developmental reorganization and unmasks responder subsets of microglia. Glia 60, 1930–1943 (2012).

    PubMed  Google Scholar 

  16. Ravasi, T. et al. Generation of diversity in the innate immune system: macrophage heterogeneity arises from gene-autonomous transcriptional probability of individual inducible genes. J. Immunol. 168, 44–50 (2002).

    CAS  PubMed  Google Scholar 

  17. Combrinck, M. I., Perry, V. H. & Cunningham, C. Peripheral infection evokes exaggerated sickness behaviour in pre-clinical murine prion disease. Neuroscience 112, 7–11 (2002).

    CAS  PubMed  Google Scholar 

  18. Cunningham, C., Wilcockson, D. C., Campion, S., Lunnon, K. & Perry, V. H. Central and systemic endotoxin challenges exacerbate the local inflammatory response and increase neuronal death during chronic neurodegeneration. J. Neurosci. 25, 9275–9284 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Cunningham, C. et al. Systemic inflammation induces acute behavioral and cognitive changes and accelerates neurodegenerative disease. Biol. Psychiatry 65, 304–312 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Field, R., Campion, S., Warren, C., Murray, C. & Cunningham, C. Systemic challenge with the TLR3 agonist poly I:C induces amplified IFNα/β and IL-1β responses in the diseased brain and exacerbates chronic neurodegeneration. Brain Behav. Immun. 24, 996–1007 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Cunningham, C. Microglia and neurodegeneration: the role of systemic inflammation. Glia 61, 71–90 (2013).

    PubMed  Google Scholar 

  22. Püntener, U., Booth, S. G., Perry, V. H. & Teeling, J. L. Long-term impact of systemic bacterial infection on the cerebral vasculature and microglia. J. Neuroinflammation 9, 146 (2012).

    PubMed  PubMed Central  Google Scholar 

  23. Ohmoto, Y. et al. Variation in the immune response to adenoviral vectors in the brain: influence of mouse strain, environmental conditions and priming. Gene Ther. 6, 471–481 (1999).

    CAS  PubMed  Google Scholar 

  24. McColl, B. W., Rothwell, N. J. & Allan, S. M. Systemic inflammatory stimulus potentiates the acute phase and CXC chemokine responses to experimental stroke and exacerbates brain damage via interleukin-1- and neutrophil-dependent mechanisms. J. Neurosci. 27, 4403–4412 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Maitra, U. et al. Molecular mechanisms responsible for the selective and low-grade induction of proinflammatory mediators in murine macrophages by lipopolysaccharide. J. Immunol. 189, 1014–1023 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Khalif, I. L., Quigley, E. M., Konovitch, E. A. & Maximova, I. D. Alterations in the colonic flora and intestinal permeability and evidence of immune activation in chronic constipation. Dig. Liver Dis. 37, 838–849 (2005).

    CAS  PubMed  Google Scholar 

  27. Khoo, T. K. et al. The spectrum of nonmotor symptoms in early Parkinson disease. Neurology 80, 276–281 (2013).

    PubMed  PubMed Central  Google Scholar 

  28. Correale, J. & Farez, M. Association between parasite infection and immune responses in multiple sclerosis. Ann. Neurol. 61, 97–108 (2007).

    CAS  PubMed  Google Scholar 

  29. Buljevac, D. et al. Prospective study on the relationship between infections and multiple sclerosis exacerbations. Brain 125, 952–960 (2002).

    CAS  PubMed  Google Scholar 

  30. Schroder, K., Sweet, M. J. & Hume, D. A. Signal integration between IFNγ and TLR signalling pathways in macrophages. Immunobiology 211, 511–524 (2006).

    CAS  PubMed  Google Scholar 

  31. Chapoval, A. I., Kamdar, S. J., Kremlev, S. G. & Evans, R. CSF-1 (M-CSF) differentially sensitizes mononuclear phagocyte subpopulations to endotoxin in vivo: a potential pathway that regulates the severity of gram-negative infections. J. Leukoc. Biol. 63, 245–252 (1998).

    CAS  PubMed  Google Scholar 

  32. Rankine, E. L., Hughes, P. M., Botham, M. S., Perry, V. H. & Felton, L. M. Brain cytokine synthesis induced by an intraparenchymal injection of LPS is reduced in MCP-1-deficient mice prior to leucocyte recruitment. Eur. J. Neurosci. 24, 77–86 (2006).

    CAS  PubMed  Google Scholar 

  33. Bhattacharyya, S. et al. Chemokine-induced leishmanicidal activity in murine macrophages via the generation of nitric oxide. J. Infect. Dis. 185, 1704–1708 (2002).

    CAS  PubMed  Google Scholar 

  34. Greter, M. et al. Stroma-derived interleukin-34 controls the development and maintenance of Langerhans cells and the maintenance of microglia. Immunity. 37, 1050–1060 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Wang, Y. et al. IL-34 is a tissue-restricted ligand of CSF1R required for the development of Langerhans cells and microglia. Nat. Immunol. 13, 753–760 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Gómez-Nicola, D., Fransen, N. L., Suzzi, S. & Perry, V. H. Regulation of microglial proliferation during chronic neurodegeneration. J. Neurosci. 33, 2481–2493 (2013).

    PubMed  PubMed Central  Google Scholar 

  37. Hinojosa, A. E., Garcia-Bueno, B., Leza, J. C. & Madrigal, J. L. CCL2/MCP-1 modulation of microglial activation and proliferation. J. Neuroinflammation 5, 77 (2011).

    Google Scholar 

  38. Krstic, D. et al. Systemic immune challenges trigger and drive Alzheimer-like neuropathology in mice. J. Neuroinflammation 9, 151 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Lunnon, K. et al. Systemic inflammation modulates Fc receptor expression on microglia during chronic neurodegeneration. J. Immunol. 186, 7215–7224 (2011).

    CAS  PubMed  Google Scholar 

  40. Boche, D., Denham, N., Holmes, C. & Nicoll, J. A. Neuropathology after active Aβ42 immunotherapy: implications for Alzheimer's disease pathogenesis. Acta Neuropathol. 120, 369–384 (2010).

    CAS  PubMed  Google Scholar 

  41. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Pott Godoy, M. C., Ferrari, C. C. & Pitossi, F. J. Nigral neurodegeneration triggered by striatal AdIL-1 administration can be exacerbated by systemic IL-1 expression. J. Neuroimmunol. 222, 29–39 (2010).

    CAS  PubMed  Google Scholar 

  43. Moreno, B. et al. Systemic inflammation induces axon injury during brain inflammation. Ann. Neurol. 70, 932–942 (2011).

    CAS  PubMed  Google Scholar 

  44. Warren, H. S. et al. Resilience to bacterial infection: difference between species could be due to proteins in serum. J. Infect. Dis. 201, 223–232 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Taveira da Silva, A. M. et al. Brief report: shock and multiple-organ dysfunction after self-administration of Salmonella endotoxin. N. Engl. J. Med. 328, 1457–1460 (1993).

    CAS  PubMed  Google Scholar 

  46. Sauter, C. & Wolfensberger, C. Interferon in human serum after injection of endotoxin. Lancet 2, 852–853 (1980).

    CAS  PubMed  Google Scholar 

  47. Brydon, L., Harrison, N. A., Walker, C., Steptoe, A. & Critchley, H. D. Peripheral inflammation is associated with altered substantia nigra activity and psychomotor slowing in humans. Biol. Psychiatry 63, 1022–1029 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Harrison, N. A. et al. Inflammation causes mood changes through alterations in subgenual cingulate activity and mesolimbic connectivity. Biol. Psychiatry 66, 407–414 (2009).

    PubMed  PubMed Central  Google Scholar 

  49. Hannestad, J. et al. Endotoxin-induced systemic inflammation activates microglia: [11C] PBR28 positron emission tomography in nonhuman primates. Neuroimage 63, 232–239 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Drake, C. et al. Brain inflammation is induced by co-morbidities and risk factors for stroke. Brain Behav. Immun. 25, 1113–1122 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Thaler, J. P. et al. Obesity is associated with hypothalamic injury in rodents and humans. J. Clin. Invest. 122, 153–162 (2012).

    CAS  PubMed  Google Scholar 

  52. Li, J., Tang, Y. & Cai, D. IKKβ/NF-κB disrupts adult hypothalamic neural stem cells to mediate a neurodegenerative mechanism of dietary obesity and pre-diabetes. Nat. Cell Biol. 14, 999–1012 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Zhang, G. et al. Hypothalamic programming of systemic ageing involving IKK-β, NF-κB and GnRH. Nature 497, 211–216 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Casserly, I. & Topol, E. Convergence of atherosclerosis and Alzheimer's disease: inflammation, cholesterol, and misfolded proteins. Lancet 363, 1139–1146 (2004).

    CAS  PubMed  Google Scholar 

  55. Balakrishnan, K. et al. Plasma Aβ42 correlates positively with increased body fat in healthy individuals. J. Alzheimers Dis. 8, 269–282 (2005).

    CAS  PubMed  Google Scholar 

  56. Donath, M. Y. & Shoelson, S. E. Type 2 diabetes as an inflammatory disease. Nat. Rev. Immunol. 11, 98–107 (2011).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Kaneko, M., Sano, K., Nakayama, J. & Amano, N. Nasu–Hakola disease: the first case reported by Nasu and review. Neuropathology 30, 463–470 (2010).

    PubMed  Google Scholar 

  59. Chitu, V. & Stanley, E. R. Colony-stimulating factor-1 in immunity and inflammation. Curr. Opin. Immunol. 18, 39–48 (2006).

    CAS  PubMed  Google Scholar 

  60. Nicholson, A. M. et al. CSF1R mutations link POLD and HDLS as a single disease entity. Neurology 12, 1033–1040 (2013).

    Google Scholar 

  61. Franceschi, C. et al. Inflammaging and anti-inflammaging: a systemic perspective on aging and longevity emerged from studies in humans. Mech. Ageing Dev. 128, 92–105 (2007).

    CAS  PubMed  Google Scholar 

  62. Clark, I. A. & Atwood, C. S. Is TNF a link between aging-related reproductive endocrine dyscrasia and Alzheimer's disease? J. Alzheimers Dis. 27, 691–699 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Butchart, J., Birch, B., Bassily, R., Wolfe, L. & Holmes, C. Male sex hormones and systemic inflammation in Alzheimer disease. Alzheimer Dis. Assoc. Disord. 27, 153–156 (2013).

    CAS  PubMed  Google Scholar 

  64. Cribbs, D. H. et al. Extensive innate immune gene activation accompanies brain aging, increasing vulnerability to cognitive decline and neurodegeneration: a microarray study. J. Neuroinflammation 9, 179 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Lemstra, A. W. et al. Microglia activation in sepsis: a case-control study. J. Neuroinflammation 15, 4 (2007).

    Google Scholar 

  66. Sudduth, T. L., Schmitt, F. A., Nelson, P. T. & Wilcock, D. M. Neuroinflammatory phenotype in early Alzheimer's disease. Neurobiol. Aging 34, 1051–1059 (2013).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  68. Boyle, P. A. et al. Physical frailty is associated with incident mild cognitive impairment in community-based older persons. J. Am. Geriatr. Soc. 58, 248–255 (2010).

    PubMed  PubMed Central  Google Scholar 

  69. Anand, S., Johansen, K. L. & Kurella Tamura, M. Aging and chronic kidney disease: the impact on physical function and cognition. J. Gerontol. A Biol. Sci. Med. Sci. 69, 315–322 (2014).

    PubMed  Google Scholar 

  70. Marioni, R. E. et al. Association between raised inflammatory markers and cognitive decline in elderly people with type 2 diabetes: the Edinburgh Type 2 Diabetes Study. Diabetes 59, 710–713 (2010).

    CAS  PubMed  Google Scholar 

  71. Barnett, K. et al. Epidemiology of multimorbidity and implications for health care, research, and medical education: a cross-sectional study. Lancet 380, 37–43 (2012).

    PubMed  Google Scholar 

  72. Holmes, C. et al. Systemic inflammation and disease progression in Alzheimer disease. Neurology 73, 768–774 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Holmes, C., Cunningham, C., Zotova, E., Culliford, D. & Perry, V. H. Proinflammatory cytokines, sickness behavior, and Alzheimer disease. Neurology 77, 212–218 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Barger, S. W. & Harmon, A. D. Microglial activation by Alzheimer amyloid precursor protein and modulation by apolipoprotein E. Nature 388, 878–881 (1997).

    CAS  PubMed  Google Scholar 

  75. Itzhaki, R. F. & Wozniak, M. A. Herpes simplex virus type 1, apolipoprotein E, and cholesterol: a dangerous liaison in Alzheimer's disease and other disorders. Prog. Lipid Res. 45, 73–90 (2006).

    CAS  PubMed  Google Scholar 

  76. Gerard, H. C. et al. The load of Chlamydia pneumoniae in the Alzheimer's brain varies with APOE genotype. Microb. Pathog. 39, 9–26 (2005).

    Google Scholar 

  77. Moretti, E. W. et al. APOE polymorphism is associated with risk of severe sepsis in surgical patients. Crit. Care Med. 33, 2521–2526 (2005).

    CAS  PubMed  Google Scholar 

  78. Harold, D. et al. Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease. Nat. Genet. 41, 1088–1093 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Lambert, J. C. et al. Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease. Nat. Genet. 41, 1094–1109 (2009).

    CAS  PubMed  Google Scholar 

  80. Nuutinen, T., Suuronen, T., Kauppinen, A. & Salminen, A. Clusterin: a forgotten player in Alzheimer's disease. Brain Res. Rev. 61, 89–104 (2009).

    CAS  PubMed  Google Scholar 

  81. Jones, L. et al. Genetic evidence implicates the immune system and cholesterol metabolism in the aetiology of Alzheimer's disease. PLoS ONE 15, e13950 (2010).

    Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Naj, A. C. et al. Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease. Nat. Genet. 43, 436–441 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Ishibashi, K., Suzuki, M., Sasaki, S. & Imai, M. Identification of a new multigene four-transmembrane family (MS4A) related to CD20, HTm4 and β subunit of the high-affinity IgE receptor. Gene 264, 87–93 (2001).

    CAS  PubMed  Google Scholar 

  86. Tanaka, N., Abe-Dohmae, S., Iwamoto, N. & Yokoyama, S. Roles of ATP-binding cassette transporter A7 in cholesterol homeostasis and host defense system. J. Atheroscler. Thromb. 18, 274–281 (2011).

    CAS  PubMed  Google Scholar 

  87. Dustin, M. L. et al. A novel adaptor protein orchestrates receptor patterning and cytoskeletal polarity in T-cell contacts. Cell 94, 667–677 (1998).

    CAS  PubMed  Google Scholar 

  88. Aasheim, H. C., Delabie, J. & Finne, E. F. Ephrin-A1 binding to CD4+ T lymphocytes stimulates migration and induces tyrosine phosphorylation of PYK2. Blood 105, 2869–2876 (2005).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  90. 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 

  91. Neumann, H. & Takahashi, K. Essential role of the microglial triggering receptor expressed on myeloid cells-2 (TREM2) for central nervous tissue immune homeostasis. J. Neuroimmunol. 184, 92–99 (2007).

    CAS  PubMed  Google Scholar 

  92. Rogers, J. et al. Clinical trial of indomethacin in Alzheimer's disease. Neurology 43, 1609–1611 (1993).

    CAS  PubMed  Google Scholar 

  93. de Jong, D. et al. No effect of one-year treatment with indomethacin on Alzheimer's disease progression: a randomized controlled trial. PLoS ONE 23, e1475 (2008).

    Google Scholar 

  94. Aisen, P. S. et al. Effects of rofecoxib or naproxen vs placebo on Alzheimer disease progression: a randomized controlled trial. JAMA 289, 2819–2826 (2003).

    CAS  PubMed  Google Scholar 

  95. 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 

  96. Simons, M. et al. Treatment with simvastatin in normocholesterolemic patients with Alzheimer's disease: a 26-week randomized, placebo-controlled, double-blind trial. Ann. Neurol. 52, 346–350 (2002).

    CAS  PubMed  Google Scholar 

  97. Sparks, D. L. et al. Atorvastatin for the treatment of mild to moderate Alzheimer disease: preliminary results. Arch. Neurol. 62, 753–757 (2005).

    PubMed  Google Scholar 

  98. Feldman, H. H. et al. Randomized controlled trial of atorvastatin in mild to moderate Alzheimer disease: LEADe. Neurology 74, 956–964 (2010).

    CAS  PubMed  Google Scholar 

  99. Aisen, P. S. et al. A randomized controlled trial of prednisone in Alzheimer's disease. Alzheimer's Disease Cooperative Study. Neurology 54, 588–593 (2000).

    CAS  PubMed  Google Scholar 

  100. Wong, W. B., Lin, V. W., Boudreau, D. & Devine, E. B. Statins in the prevention of dementia and Alzheimer's disease: a meta-analysis of observational studies and an assessment of confounding. Pharmacoepidemiol. Drug Safety 22, 345–358 (2013).

    CAS  Google Scholar 

  101. Stewart, W. F., Kawas, C., Corrada, M. & Metter, E. J. Risk of Alzheimer's disease and duration of NSAID use. Neurology 48, 626–632 (1997).

    CAS  PubMed  Google Scholar 

  102. McGeer, P. L., Schulzer, M. & McGeer, E. G. Arthritis and anti-inflammatory agents as possible protective factors for Alzheimer's disease: a review of 17 epidemiologic studies. Neurology 47, 425–432 (1996).

    CAS  PubMed  Google Scholar 

  103. Vlad, S. C., Miller, D. R., Kowall, N. W. & Felson, D. T. Protective effects of NSAIDs on the development of Alzheimer disease. Neurology 70, 1672–1677 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Chou, R., Kane, M., Ghimire, S. & Gautam, S. Tumour necrosis factor inhibition reduces the incidence of Alzheimer's disease in rheumatoid arthritis patients. Presented at American College of Rheumatology (2010).

  105. Grande, G. et al. Physical activity reduces the risk of dementia in mild cognitive impairment subjects: a cohort study. J. Alzheimers Dis. http://dx.doi.org/10.3233/JAD-131808.

  106. Pedersen, B. K. Muscle as a secretory organ. Compr. Physiol. 3, 1337–1362 (2013).

    PubMed  Google Scholar 

  107. Browne, T. C. et al. IFN-γ production by amyloid β-specific Th1 cells promotes microglial activation and increases plaque burden in a mouse model of Alzheimer's disease. J. Immunol. 190, 2241–2251 (2013).

    CAS  PubMed  Google Scholar 

  108. 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 

  109. Lawson, L. J., Perry, V. H. & Gordon, S. Turnover of resident microglia in the normal adult mouse brain. Neuroscience 48, 405–415 (1992).

    CAS  PubMed  Google Scholar 

  110. Mildner, A. et al. Distinct and non-redundant roles of microglia and myeloid subsets in mouse models of Alzheimer's disease. J. Neurosci. 31, 11159–11171 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Hart, A. D., Wyttenbach, A., Perry, V. H. & Teeling, J. L. Age related changes in microglial phenotype vary between CNS regions: grey versus white matter differences. Brain Behav. Immun. 26, 754–765 (2012).

    PubMed  PubMed Central  Google Scholar 

  112. Lawson, L. J., Perry, V. H., Dri, P. & Gordon, S. Heterogeneity in the distribution and morphology of microglia in the normal adult mouse brain. Neuroscience 39, 151–170 (1990).

    CAS  PubMed  Google Scholar 

  113. Mittelbronn, M., Dietz, K., Schluesener, H. J. & Meyermann, R. Local distribution of microglia in the normal adult human central nervous system differs by up to one order of magnitude. Acta Neuropathol. 101, 249–255 (2001).

    CAS  PubMed  Google Scholar 

  114. Mouton, P. R. et al. Age and gender effects on microglia and astrocyte numbers in brains of mice. Brain Res. 956, 30–35 (2002).

    CAS  PubMed  Google Scholar 

  115. Sheng, J. G., Mrak, R. E. & Griffin, W. S. Enlarged and phagocytic, but not primed, interleukin-1α immunoreactive microglia increase with age in normal human brain. Acta Neuropath. 95, 229–234 (1998).

    CAS  PubMed  Google Scholar 

  116. Hoek, R. M. et al. Down-regulation of the macrophage lineage through interaction with OX2 (CD200). Science 290, 1768–1771 (2000).

    CAS  PubMed  Google Scholar 

  117. Cardona, A. E. et al. Control of microglial neurotoxicity by the fractalkine receptor. Nat. Neurosci. 9, 917–924 (2006).

    CAS  PubMed  Google Scholar 

  118. Gitik, M., Liraz-Zaltsman, S., Oldenberg, P.-A., Reichert, F. & Rotshenker, S. Myelin downregulates myelin phagocytosis by microglia and macrophages through interactions between CD47 and SIRPα (signal regulatory protein-α) on phagocytes. J. Neuroinflammation 8, 24 (2011).

    PubMed  PubMed Central  Google Scholar 

  119. Wang, Y. & Neumann, H. Alleviation of neurotoxicity by microglial human Siglec-11. J. Neurosci. 30, 3482–3488 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors' research work is supported by grants from Alzheimer's Society and Alzheimer's Research Trust UK (V.H.P. and C.H.), and by funding from the Medical Research Council and Wellcome Trust (V.H.P.).

Author information

Authors and Affiliations

Authors

Contributions

V.H.P. and C.H. researched data for the article, wrote the article, and undertook reviewing and editing of the manuscript before submission.

Corresponding author

Correspondence to V. Hugh Perry.

Ethics declarations

Competing interests

V.H.P. and C.H. have received an independent investigator grant from Pfizer to determine the safety and tolerability of etanercept in patients with Alzheimer disease.

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Perry, V., Holmes, C. Microglial priming in neurodegenerative disease. Nat Rev Neurol 10, 217–224 (2014). https://doi.org/10.1038/nrneurol.2014.38

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrneurol.2014.38

Further reading

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