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β-amyloid, microglia, and the inflammasome in Alzheimer’s disease


There is extensive evidence that accumulation of mononuclear phagocytes including microglial cells, monocytes, and macrophages at sites of β-amyloid (Aβ) deposition in the brain is an important pathological feature of Alzheimer’s disease (AD) and related animal models, and the concentration of these cells clustered around Aβ deposits is several folds higher than in neighboring areas of the brain [1–5]. Microglial cells phagocytose and clear debris, pathogens, and toxins, but they can also be activated to produce inflammatory cytokines, chemokines, and neurotoxins [6]. Over the past decade, the roles of microglial cells in AD have begun to be clarified, and we proposed that these cells play a dichotomous role in the pathogenesis of AD [4, 6–11]. Microglial cells are able to clear soluble and fibrillar Aβ, but continued interactions of these cells with Aβ can lead to an inflammatory response resulting in neurotoxicity. Inflammasomes are inducible high molecular weight protein complexes that are involved in many inflammatory pathological processes. Recently, Aβ was found to activate the NLRP3 inflammasome in microglial cells in vitro and in vivo thereby defining a novel pathway that could lead to progression of AD [12–14]. In this manuscript, we review possible steps leading to Aβ-induced inflammasome activation and discuss how this could contribute to the pathogenesis of AD.

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  1. 1.

    McGeer PL et al (1987) Reactive microglia in patients with senile dementia of the Alzheimer type are positive for the histocompatibility glycoprotein HLA-DR. Neurosci Lett 79(1-2):195–200

  2. 2.

    Rozemuller JM, Eikelenboom P, Stam FC (1986) Role of microglia in plaque formation in senile dementia of the Alzheimer type. An immunohistochemical study. Virchows Arch B Cell Pathol Incl Mol Pathol 51(3):247–54

  3. 3.

    Frautschy SA et al (1998) Microglial response to amyloid plaques in APPsw transgenic mice. Am J Pathol 152(1):307–17

  4. 4.

    Hickman SE, Allison EK, El Khoury J (2008) Microglial dysfunction and defective beta-amyloid clearance pathways in aging Alzheimer's disease mice. J Neurosci 28(33):8354–60

  5. 5.

    El Khoury J (2010) Neurodegeneration and the neuroimmune system. Nat Med 16(12):1369–70

  6. 6.

    Kettenmann H et al (2011) Physiology of microglia. Physiol Rev 91(2):461–553

  7. 7.

    El Khoury J, Luster AD (2008) Mechanisms of microglia accumulation in Alzheimer's disease: therapeutic implications. Trends Pharmacol Sci 29(12):626–32

  8. 8.

    El Khoury J et al (2007) Ccr2 deficiency impairs microglial accumulation and accelerates progression of Alzheimer-like disease. Nat Med 13(4):432–8

  9. 9.

    El Khoury JB et al (2003) CD36 mediates the innate host response to beta-amyloid. J Exp Med 197(12):1657–66

  10. 10.

    Frenkel D et al (2013) Scara1 deficiency impairs clearance of soluble amyloid-beta by mononuclear phagocytes and accelerates Alzheimer's-like disease progression. Nat Commun 4:2030

  11. 11.

    Stewart CR et al (2010) CD36 ligands promote sterile inflammation through assembly of a Toll-like receptor 4 and 6 heterodimer. Nat Immunol 11(2):155–61

  12. 12.

    Halle A et al (2008) The NALP3 inflammasome is involved in the innate immune response to amyloid-beta. Nat Immunol 9(8):857–65

  13. 13.

    Heneka MT et al (2013) NLRP3 is activated in Alzheimer's disease and contributes to pathology in APP/PS1 mice. Nature 493(7434):674–8

  14. 14.

    Sheedy FJ et al (2013) CD36 coordinates NLRP3 inflammasome activation by facilitating intracellular nucleation of soluble ligands into particulate ligands in sterile inflammation. Nat Immunol 14(8):812–20

  15. 15.

    Lawson LJ et al (1990) Heterogeneity in the distribution and morphology of microglia in the normal adult mouse brain. Neuroscience 39(1):151–70

  16. 16.

    Hickman SE et al (2013) The microglial sensome revealed by direct RNA sequencing. Nat Neurosci 16(12):1896–905

  17. 17.

    Stence N, Waite M, Dailey ME (2001) Dynamics of microglial activation: a confocal time-lapse analysis in hippocampal slices. Glia 33(3):256–66

  18. 18.

    Mogi M et al (1994) Interleukin-1 beta, interleukin-6, epidermal growth factor and transforming growth factor-alpha are elevated in the brain from Parkinsonian patients. Neurosci Lett 180(2):147–50

  19. 19.

    Morimoto K et al (2011) Expression profiles of cytokines in the brains of Alzheimer's disease (AD) patients compared to the brains of non-demented patients with and without increasing AD pathology. J Alzheimers Dis 25(1):59–76

  20. 20.

    Stoeck K, Bodemer M, Zerr I (2006) Pro- and anti-inflammatory cytokines in the CSF of patients with Creutzfeldt-Jakob disease. J Neuroimmunol 172(1-2):175–81

  21. 21.

    Coraci IS et al (2002) CD36, a class B scavenger receptor, is expressed on microglia in Alzheimer's disease brains and can mediate production of reactive oxygen species in response to beta-amyloid fibrils. Am J Pathol 160(1):101–12

  22. 22.

    Cunningham C (2013) Microglia and neurodegeneration: the role of systemic inflammation. Glia 61(1):71–90

  23. 23.

    Cho S et al (2001) Repression of proinflammatory cytokine and inducible nitric oxide synthase (NOS2) gene expression in activated microglia by N-acetyl-O-methyldopamine: protein kinase A-dependent mechanism. Glia 33(4):324–33

  24. 24.

    Yates SL et al (2000) Amyloid beta and amylin fibrils induce increases in proinflammatory cytokine and chemokine production by THP-1 cells and murine microglia. J Neurochem 74(3):1017–25

  25. 25.

    Goodwin JL, Kehrli ME Jr, Uemura E (1997) Integrin Mac-1 and beta-amyloid in microglial release of nitric oxide. Brain Res 768(1-2):279–86

  26. 26.

    Martinon F, Burns K, Tschopp J (2002) The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol Cell 10(2):417–26

  27. 27.

    Boyden ED, Dietrich WF (2006) Nalp1b controls mouse macrophage susceptibility to anthrax lethal toxin. Nat Genet 38(2):240–4

  28. 28.

    Mariathasan S et al (2006) Cryopyrin activates the inflammasome in response to toxins and ATP. Nature 440(7081):228–32

  29. 29.

    Mariathasan S et al (2004) Differential activation of the inflammasome by caspase-1 adaptors ASC and Ipaf. Nature 430(6996):213–8

  30. 30.

    Rathinam VA et al (2010) The AIM2 inflammasome is essential for host defense against cytosolic bacteria and DNA viruses. Nat Immunol 11(5):395–402

  31. 31.

    Gross O et al (2009) Syk kinase signalling couples to the Nlrp3 inflammasome for anti-fungal host defence. Nature 459(7245):433–6

  32. 32.

    Rathinam VA et al (2012) TRIF licenses caspase-11-dependent NLRP3 inflammasome activation by gram-negative bacteria. Cell 150(3):606–19

  33. 33.

    Martinon F et al (2006) Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 440(7081):237–41

  34. 34.

    Duewell P et al (2010) NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature 464(7293):1357–61

  35. 35.

    Garlanda C, Dinarello CA, Mantovani A (2013) The interleukin-1 family: back to the future. Immunity 39(6):1003–18

  36. 36.

    Lynch MA (2010) Age-related neuroinflammatory changes negatively impact on neuronal function. Front Aging Neurosci 1:6

  37. 37.

    Bauernfeind FG et al (2009) Cutting edge: NF-kappaB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression. J Immunol 183(2):787–91

  38. 38.

    Franchi L, Eigenbrod T, Nunez G (2009) Cutting edge: TNF-alpha mediates sensitization to ATP and silica via the NLRP3 inflammasome in the absence of microbial stimulation. J Immunol 183(2):792–6

  39. 39.

    Chow JC et al (1999) Toll-like receptor-4 mediates lipopolysaccharide-induced signal transduction. J Biol Chem 274(16):10689–92

  40. 40.

    Juliana C et al (2012) Non-transcriptional priming and deubiquitination regulate NLRP3 inflammasome activation. J Biol Chem 287(43):36617–22

  41. 41.

    Duncan JA et al (2007) Cryopyrin/NALP3 binds ATP/dATP, is an ATPase, and requires ATP binding to mediate inflammatory signaling. Proc Natl Acad Sci U S A 104(19):8041–6

  42. 42.

    Srinivasula SM et al (2002) The PYRIN-CARD protein ASC is an activating adaptor for caspase-1. J Biol Chem 277(24):21119–22

  43. 43.

    Baroja-Mazo A et al (2014) The NLRP3 inflammasome is released as a particulate danger signal that amplifies the inflammatory response. Nat Immunol 15(8):738–48

  44. 44.

    Franklin BS et al (2014) The adaptor ASC has extracellular and ‘prionoid’ activities that propagate inflammation. Nat Immunol 15(8):727–37

  45. 45.

    Yan Y et al (2015) Dopamine Controls Systemic Inflammation through Inhibition of NLRP3 Inflammasome. Cell 160(1-2):62–73

  46. 46.

    Sarkar C et al (2010) The immunoregulatory role of dopamine: an update. Brain Behav Immun 24(4):525–8

  47. 47.

    Lee GS et al (2012) The calcium-sensing receptor regulates the NLRP3 inflammasome through Ca2+ and cAMP. Nature 492(7427):123–7

  48. 48.

    Coll RC et al (2015) A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases. Nat Med 21(3):248–255

  49. 49.

    Griffin WS et al (1989) Brain interleukin 1 and S-100 immunoreactivity are elevated in Down syndrome and Alzheimer disease. Proc Natl Acad Sci U S A 86(19):7611–5

  50. 50.

    Murphy N, Grehan B, Lynch MA (2014) Glial uptake of amyloid beta induces NLRP3 inflammasome formation via cathepsin-dependent degradation of NLRP10. Neuromol Med 16(1):205–15

  51. 51.

    Kahlenberg JM, Dubyak GR (2004) Mechanisms of caspase-1 activation by P2X7 receptor-mediated K+ release. Am J Physiol Cell Physiol 286(5):C1100–8

  52. 52.

    McLarnon JG et al (2006) Upregulated expression of purinergic P2X(7) receptor in Alzheimer disease and amyloid-beta peptide-treated microglia and in peptide-injected rat hippocampus. J Neuropathol Exp Neurol 65(11):1090–7

  53. 53.

    Kahlenberg JM et al (2005) Potentiation of caspase-1 activation by the P2X7 receptor is dependent on TLR signals and requires NF-kappaB-driven protein synthesis. J Immunol 175(11):7611–22

  54. 54.

    Wegiel J et al (2003) Origin and turnover of microglial cells in fibrillar plaques of APPsw transgenic mice. Acta Neuropathol 105(4):393–402

  55. 55.

    Lebson L et al (2010) Trafficking CD11b-positive blood cells deliver therapeutic genes to the brain of amyloid-depositing transgenic mice. J Neurosci 30(29):9651–8

  56. 56.

    Bennett JL et al (2003) CCL2 transgene expression in the central nervous system directs diffuse infiltration of CD45(high)CD11b(+) monocytes and enhanced Theiler's murine encephalomyelitis virus-induced demyelinating disease. J Neurovirol 9(6):623–36

  57. 57.

    Sedgwick JD et al (1991) Isolation and direct characterization of resident microglial cells from the normal and inflamed central nervous system. Proc Natl Acad Sci U S A 88(16):7438–42

  58. 58.

    Saederup N et al (2010) Selective chemokine receptor usage by central nervous system myeloid cells in CCR2-red fluorescent protein knock-in mice. PLoS One 5(10):e13693

  59. 59.

    Naert G, Rivest S (2012) Hematopoietic CC-chemokine receptor 2 (CCR2) competent cells are protective for the cognitive impairments and amyloid pathology in a transgenic mouse model of Alzheimer's disease. Mol Med 18:297–313

  60. 60.

    Jay TR et al (2015) TREM2 deficiency eliminates TREM2+ inflammatory macrophages and ameliorates pathology in Alzheimer's disease mouse models. J Exp Med 212(3):287–295

  61. 61.

    Koronyo Y et al (2015) Therapeutic effects of glatiramer acetate and grafted CD115+ monocytes in a mouse model of Alzheimer's disease. Brain 138(8):2399–2422

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Maike Gold is a postdoctoral Research Fellow of the Max Kade Foundation. Part of the work described here was supported by NIH grants NIH grants NS059005, AG032349, and AI082660 to Joseph El Khoury.

Conflict of interest

The authors declare that they have no competing interests.

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Correspondence to Joseph El Khoury.

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This article is a contribution to the Special Issue on : Role of Astrocytes and Microglia in CNS Inflammation - Guest Editor: Francisco Quintana

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Gold, M., El Khoury, J. β-amyloid, microglia, and the inflammasome in Alzheimer’s disease. Semin Immunopathol 37, 607–611 (2015).

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  • Microglia
  • Macrophage
  • NLRP3 inflammasome
  • β-amyloid
  • Alzheimer’s disease