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Der Nervenarzt

, Volume 90, Issue 9, pp 898–906 | Cite as

Neuroinflammation als Motor der Alzheimer-Erkrankung

  • Sergio Castro-Gomez
  • Julius Binder
  • Michael T. HenekaEmail author
Leitthema

Zusammenfassung

Die sporadische Alzheimer-Krankheit ist die häufigste neurodegenerative Erkrankung und stellt ein sehr relevantes Problem der öffentlichen Gesundheitsversorgung mit einer verheerenden wirtschaftlichen Belastung für die Industrieländer dar. Neue Erkenntnisse aus experimentellen, epidemiologischen, bildmorphologischen und genomweiten Assoziationsstudien („genome wide association studies“, GWAS) unterstreichen die Rolle des angeborenen Immunsystems in der Pathophysiologie dieser Krankheit. Im folgenden Artikel werden die neu entdeckten krankheitsassoziierten Gene sowie die experimentellen Beweise für die Rolle der Mikrogliazellen bei der Entstehung des Fortschreitens der Alzheimer-Krankheit diskutiert und zusammengefasst. Die Entdeckung verschiedener pathologieassoziierten Mikrogliaphänotypen sowie neuer molekularer Akteure wird die Entwicklung neuer präventiver und therapeutischer Strategien durch die Modulation der Neuroinflammation bei neurodegenerativen Erkrankungen ermöglichen.

Schlüsselwörter

Zerebrales Immunsystem Neurodegeneration Mikroglia Demenz Genetische Risikofaktoren 

Neuroinflammation as motor of Alzheimer’s disease

Abstract

Sporadic Alzheimer’s disease is the most common neurodegenerative disorder and represents a very important public healthcare problem with a devastating economic burden for industrialized countries. Recent knowledge acquired from experimental, epidemiological, radiological and genome-wide association studies (GWAS) underline the role of the innate immune system in the pathophysiology of this disease. This article reviews and discusses the function of the cerebral innate immune system, the newly discovered genes associated with the disease development and the experimental evidence around the role of microglia in the onset and progression of Alzheimer’s disease. The discovery of different microglia phenotypes associated with the pathology as well as new molecular players will enable the development of new preventive and therapeutic strategies by modulating neuroinflammation in neurodegenerative diseases.

Keywords

Cerebral immune system Neurodegeneration Microglia Dementia Genetic risk factors 

Notes

Einhaltung ethischer Richtlinien

Interessenkonflikt

M.T. Heneka weist auf folgende Beziehungen hin: Berater für IFM Therapeutics; Redakteur bei der Zeitschrift Neurology, Neuroimmunology and Neuroinflammation; Forschungsunterstützung von Schering, Actelion, Pfizer und Novartis; Honorare für Vorträge von Pfizer, Novartis, Roche, Abbvie und Biogen; Forschungsförderung der Deutschen Hermann von Helmholtz-Gemeinschaft, der Deutschen Forschungsgemeinschaft, des European Research Council, der Deutsch-Israelischen Stiftung und des National Institutes of Health (NIH). S. Castro-Gomez und J. Binder geben an, dass kein Interessenkonflikt besteht.

Für diesen Beitrag wurden von den Autoren keine Studien an Menschen oder Tieren durchgeführt. Für die aufgeführten Studien gelten die jeweils dort angegebenen ethischen Richtlinien.

Literatur

  1. 1.
    Medzhitov R (2008) Origin and physiological roles of inflammation. Nature 454:428–435CrossRefGoogle Scholar
  2. 2.
    Kierdorf K et al (2013) Microglia emerge from erythromyeloid precursors via Pu.1-and Irf8-dependent pathways. Nat Neurosci 16:273–280CrossRefGoogle Scholar
  3. 3.
    Askew K et al (2017) Coupled proliferation and Apoptosis maintain the rapid turnover of Microglia in the adult brain. Cell Rep 18:391–405CrossRefGoogle Scholar
  4. 4.
    Benarroch EE (2013) Microglia: Multiple roles in surveillance, circuit shaping, and response to injury. Baillieres Clin Neurol 81:1079–1088Google Scholar
  5. 5.
    Pierre WC et al (2017) Neonatal microglia: the cornerstone of brain fate. Brain Behav Immun 59:333–345CrossRefGoogle Scholar
  6. 6.
    Parkhurst CN et al (2013) Microglia promote learning-dependent synapse formation through brain-derived neurotrophic factor. Cell 155:1596–1609CrossRefGoogle Scholar
  7. 7.
    Querfurth HW, LaFerla FM (2010) Alzheimer’s disease. N Engl J Med 362:329–344CrossRefGoogle Scholar
  8. 8.
    Stelzmann RA, Schnitzlein HN, Murtagh FR (1995) VIEWPOINT an English translation of alzheimer’s 1907 paper „Über eine eigenartige Erkrankung der Hirnrinde“. Clin Anat 8:429–443CrossRefGoogle Scholar
  9. 9.
    Heneka MT et al (2015) Neuroinflammation in Alzheimer’s disease. Lancet Neurol 14:388–405CrossRefGoogle Scholar
  10. 10.
    Wang J et al (2015) Anti-inflammatory drugs and risk of alzheimer’s disease: an updated systematic review and meta-analysis. J Alzheimer’s Dis 44:385–396CrossRefGoogle Scholar
  11. 11.
    I. TJ, E. EW, S. DM, L. KM (2010) Long-term cognitive impairment and functional disability among survivors of severe sepsis. JAMA 304:1787–1794CrossRefGoogle Scholar
  12. 12.
    Scarmeas N et al (2009) Physical activity, diet, and risk of Alzheimer disease. JAMA 302:627–637CrossRefGoogle Scholar
  13. 13.
    Hicks A, James A, Spitz G, Ponsford J (2019) Traumatic brain injury as a risk factor for dementia and alzheimer’s disease: critical review of study methodologies. J Neurotrauma.  https://doi.org/10.1089/neu.2018.6346 Google Scholar
  14. 14.
    Kwiatek-Majkusiak J et al (2015) Relationships between typical histopathological hallmarks and the ferritin in the hippocampus from patients with Alzheimer’s disease. Acta Neurobiol Exp (wars) 75:391–398Google Scholar
  15. 15.
    Zeineh MM et al (2015) Activated iron-containing microglia in the human hippocampus identified by magnetic resonance imaging in Alzheimer disease. Neurobiol Aging 36:2483–2500CrossRefGoogle Scholar
  16. 16.
    Cosenza-Nashat M et al (2009) Expression of the translocator protein of 18 kDa by microglia, macrophages and astrocytes based on immunohistochemical localization in abnormal human brain. Neuropathol Appl Neurobiol 35:306–328CrossRefGoogle Scholar
  17. 17.
    Kreisl WC et al (2013) In vivo radioligand binding to translocator protein correlates with severity of Alzheimer’s disease. Brain 136:2228–2238CrossRefGoogle Scholar
  18. 18.
    Leroy C et al (2016) Early and protective microglial activation in Alzheimer’s disease : a prospective study using 18 F-DPA-714 PET imaging. Brain:1252–1264.  https://doi.org/10.1093/brain/aww017 Google Scholar
  19. 19.
    Kunkle BW et al (2019) Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing. Nat Genet 51:414–430CrossRefGoogle Scholar
  20. 20.
    Jansen IE et al (2019) Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer’s disease risk. Nat Genet 51:404–413CrossRefGoogle Scholar
  21. 21.
    Lambert JC et al (2013) Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease. Nat Genet 45:1452–1458CrossRefGoogle Scholar
  22. 22.
    Huang K et al (2017) A common haplotype lowers PU.1 expression in myeloid cells and delays onset of Alzheimer’s disease. Nat Neurosci 20:1052–1061CrossRefGoogle Scholar
  23. 23.
    Guerreiro R et al (2013) TREM2 variants in Alzheimer’s disease. N Engl J Med 368:117–127CrossRefGoogle Scholar
  24. 24.
    Jonsson T et al (2013) Variant of TREM2 associated with the risk of Alzheimer’s disease. N Engl J Med 368:107–116CrossRefGoogle Scholar
  25. 25.
    Wang S, Colonna M (2019) Microglia in Alzheimer’s disease: A target for immunotherapy. J Leukoc Biol:1–9.  https://doi.org/10.1002/JLB.MR0818-319R Google Scholar
  26. 26.
    Sims R, van der Lee SJ, Naj AC, Bellenguez C, Badarinarayan N, Jakobsdottir J, Kunkle BW, Boland A, Raybould R, Bis JC, Martin ER, Grenier-Boley B, Heilmann-Heimbach S, Chouraki V, Kuzma AB, Sleegers K, Vronskaya M, Ruiz A, Graham RR, Olaso R, Hoffmann P (2017) S. G. Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer’s disease. Nat Genet.  https://doi.org/10.1038/ng.3916 Google Scholar
  27. 27.
    Huang Y, Weisgraber KH, Mucke L, Mahley RW (2004) Apolipoprotein E. J Mol Neurosci 23:189–204CrossRefGoogle Scholar
  28. 28.
    Keren-shaul H et al (2017) A unique Microglia type associated with restricting development of alzheimer’s disease article A unique Microglia type associated with restricting development of alzheimer’s disease. Cell 169(7):1276–1290.e1CrossRefGoogle Scholar
  29. 29.
    Krasemann S et al (2017) The TREM2-APOE pathway drives the Transcriptional phenotype of dysfunctional Microglia in Neurodegenerative diseases. Immunity 47:566–581.e9CrossRefGoogle Scholar
  30. 30.
    Mathys H et al (2019) Single-cell transcriptomic analysis of Alzheimer’s disease. Nature.  https://doi.org/10.1038/s41586-019-1195-2 Google Scholar
  31. 31.
    Dickson DW et al (1988) Alzheimer’s disease. A double-labeling immunohistochemical study of senile plaques. Am J Pathol 132:86–101Google Scholar
  32. 32.
    Martin E, Boucher C, Fontaine B, Delarasse C (2017) Distinct inflammatory phenotypes of microglia and monocyte-derived macrophages in Alzheimer’s disease models: effects of aging and amyloid pathology. Aging Cell 16:27–38CrossRefGoogle Scholar
  33. 33.
    Venegas C, Heneka MT (2017) Danger-associated molecular patterns in Alzheimer’s disease. J Leukoc Biol 101:87–98CrossRefGoogle Scholar
  34. 34.
    Du Yan S et al (1996) RAGE and amyloid-β peptide neurotoxicity in Alzheimer’s disease. Nature 382:685–691CrossRefGoogle Scholar
  35. 35.
    Landreth GE, Reed-geaghan EG (2009) Toll-like receptors: roles in infection and neuropathology Bd. 336. Springer, Berlin HeidelbergGoogle Scholar
  36. 36.
    El Khoury J et al (1996) Scavenger receptor-mediated adhesion of microglia to β‑amyloid fibrils. Nature 382:716–719CrossRefGoogle Scholar
  37. 37.
    Bamberger ME, Harris ME, McDonald DR, Husemann J, Landreth GE (2003) A cell surface receptor complex for fibrillar beta-amyloid mediates microglial activation. J Neurosci 23:2665–2674CrossRefGoogle Scholar
  38. 38.
    Halle A et al (2008) The NALP3 inflammasome is involved in the innate immune response to amyloid-β. Nat Immunol 9:857–865CrossRefGoogle Scholar
  39. 39.
    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 14:812–820CrossRefGoogle Scholar
  40. 40.
    Venegas C et al (2017) Microglia-derived ASC specks cross-seed amyloid-β in Alzheimer’s disease. Nature 552:355–361CrossRefGoogle Scholar
  41. 41.
    Asai H et al (2015) Depletion of microglia and inhibition of exosome synthesis halt tau propagation. Nat Neurosci 18:1584–1593CrossRefGoogle Scholar
  42. 42.
    Liddelow SA et al (2017) Neurotoxic reactive astrocytes are induced by activated microglia. Nature 541:481–487CrossRefGoogle Scholar
  43. 43.
    Bisht K et al (2016) Dark microglia: a new phenotype predominantly associated with pathological states. Glia 64:826–839CrossRefGoogle Scholar
  44. 44.
    Füger P et al (2017) Microglia turnover with aging and in an Alzheimer’s model via long-term in vivo single-cell imaging. Nat Neurosci 20:1371–1376CrossRefGoogle Scholar
  45. 45.
    Olmos-Alonso A et al (2016) Pharmacological targeting of CSF1R inhibits microglial proliferation and prevents the progression of Alzheimer’s-like pathology. Brain 139:891–907CrossRefGoogle Scholar
  46. 46.
    Kamphuis W, Orre M, Kooijman L, Dahmen M, Hol EM (2012) Differential cell proliferation in the cortex of the APPswePS1dE9 Alzheimer’s disease mouse model. Glia 60:615–629CrossRefGoogle Scholar
  47. 47.
    Frank S, Copanaki E, Burbach GJ, Müller UC, Deller T (2009) Differential regulation of toll-like receptor mRNAs in amyloid plaque-associated brain tissue of aged APP23 transgenic mice. Neurosci Lett 453:41–44CrossRefGoogle Scholar
  48. 48.
    Song M, Jin J, Lim JE et al (2011) TLR4 mutation reduces microglial activation, increases Abeta deposits and exacerbates cognitive deficits in a mouse model of Alzheimer’s disease. J Neuroinflammation 8:92.  https://doi.org/10.1186/1742-2094-8-92 CrossRefGoogle Scholar
  49. 49.
    Reed-Geaghan EG, Reed QW, Cramer PE, Landreth GE (2010) Deletion of CD14 attenuates alzheimer’s disease pathology by influencing the brain’s inflammatory milieu. J Neurosci 30:15369–15373CrossRefGoogle Scholar
  50. 50.
    Wang YL et al (2013) Toll-like receptor 9 promoter polymorphism is associated with decreased risk of Alzheimer’s disease in Han Chinese. J Neuroinflammation 10:1–5CrossRefGoogle Scholar
  51. 51.
    Harold D et al (2009) Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer’s disease. Nat Genet 41:1088–1093CrossRefGoogle Scholar
  52. 52.
    Lambert JC et al (2009) Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer’s disease. Nat Genet 41:1094–1099CrossRefGoogle Scholar
  53. 53.
    Hong S et al (2016) Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science 80(352):712–716CrossRefGoogle Scholar
  54. 54.
    Yin C et al (2019) ApoE attenuates unresolvable inflammation by complex formation with activated C1q. Nat Med 25:496–506CrossRefGoogle Scholar
  55. 55.
    Griffin WST, Mrak RE (2002) Interleukin-1 in the genesis and progression of and risk for development of neuronal degeneration in Alzheimer’s disease. J Leukoc Biol 72:233–238Google Scholar
  56. 56.
    Ghosh S et al (2013) Sustained Interleukin-1  Overexpression exacerbates tau pathology despite reduced Amyloid burden in an alzheimer’s mouse model. J Neurosci 33:5053–5064CrossRefGoogle Scholar
  57. 57.
    Chakrabarty P et al (2009) Massive gliosis induced by interleukin-6 suppresses Aβ deposition in vivo : evidence against inflammation as a driving force for amyloid deposition. Faseb J 24:548–559CrossRefGoogle Scholar
  58. 58.
    Chakrabarty P et al (2010) IFN-  promotes complement expression and attenuates Amyloid plaque deposition in Amyloid   precursor protein Transgenic mice. J Immunol 184:5333–5343CrossRefGoogle Scholar
  59. 59.
    Montgomery SL et al (2011) Ablation of TNF-RI/RII expression in Alzheimer’s disease mice leads to an unexpected enhancement of pathology: Implications for chronic pan-TNF-α suppressive therapeutic strategies in the brain. Am J Pathol 179:2053–2070CrossRefGoogle Scholar
  60. 60.
    Vom Berg J et al (2012) Inhibition of IL-12/IL-23 signaling reduces Alzheimer’s diseasea-like pathology and cognitive decline. Nat Med 18:1812–1819CrossRefGoogle Scholar
  61. 61.
    Zetterberg H, Andreasen N, Blennow K (2004) Increased cerebrospinal fluid levels of transforming growth factor-β1 in Alzheimer’s disease. Neurosci Lett 367:194–196CrossRefGoogle Scholar
  62. 62.
    Tesseur I et al (2006) Deficiency in neuronal TGF-β signaling promotes neurodegeneration and Alzheimer’s pathology. J Clin Invest 116:3060–3069CrossRefGoogle Scholar
  63. 63.
    Chakrabarty P et al (2015) IL-10 alters Immunoproteostasis in APP mice, increasing plaque burden and worsening cognitive behavior. Neuron 85:519–533CrossRefGoogle Scholar
  64. 64.
    Ulland TK, Colonna M (2018) TREM2—a key player in microglial biology and Alzheimer disease. Nat Rev Neurol 14:667–675CrossRefGoogle Scholar
  65. 65.
    Hsieh CL et al (2009) A role for TREM2 ligands in the phagocytosis of apoptotic neuronal cells by microglia. J Neurochem 109:1144–1156CrossRefGoogle Scholar
  66. 66.
    Suárez-Calvet M et al (2016) sTREM2 cerebrospinal fluid levels are a potential biomarker for microglia activity in early-stage Alzheimer’s disease and associate with neuronal injury markers. Embo Mol Med.  https://doi.org/10.15252/emmm.201506123 Google Scholar
  67. 67.
    Gurvit H et al (2014) TREM2 mutations implicated in neurodegeneration impair cell surface transport and phagocytosis. Sci Transl Med 6:243ra86–243ra86CrossRefGoogle Scholar
  68. 68.
    Ulland TK et al (2017) TREM2 maintains mcroglial metabolic fitness in alzheimer’s disease. Cell 170:649–663.e13CrossRefGoogle Scholar
  69. 69.
    Wang Y et al (2014) Altered microglial response to Aβ plaques in APPPS1-21 mice heterozygous for TREM2. Mol Neurodegener 9:20.  https://doi.org/10.1186/1750-1326-9-20 Google Scholar
  70. 70.
    Mazaheri F et al (2017) TREM2 deficiency impairs chemotaxis and microglial responses to neuronal injury. Embo Rep 18:1186–1198CrossRefGoogle Scholar
  71. 71.
    Song WM et al (2018) Humanized TREM2 mice reveal microglia-intrinsic and -extrinsic effects of R47H polymorphism. J Exp Med 215:745–760CrossRefGoogle Scholar
  72. 72.
    Jiang T et al (2015) Silencing of TREM2 exacerbates tau pathology, neurodegenerative changes, and spatial learning deficits in P301S tau transgenic mice. Neurobiol Aging 36:3176–3186CrossRefGoogle Scholar
  73. 73.
    Cronk JC et al (2018) Peripherally derived macrophages can engraft the brain independent of irradiation and maintain an identity distinct from microglia. J Exp Med 215:1627–1647CrossRefGoogle Scholar
  74. 74.
    Marsh SE et al (2016) The adaptive immune system restrains Alzheimer’s disease pathogenesis by modulating microglial function. Proc Natl Acad Sci U S A 113:E1316–E1325CrossRefGoogle Scholar
  75. 75.
    Katsimpardi L et al (2014) Vascular and Neurogenic rejuvenation of the aging mouse brain by young systemic factors. Science 80(344):630–634CrossRefGoogle Scholar
  76. 76.
    Domercq M, Vazquez-Villoldo N, Matute C (2013) Neurotransmitter signaling in the pathophysiology of microglia. Front Cell Neurosci 7:1–17Google Scholar
  77. 77.
    Kim TS et al (2008) Changes in the levels of plasma soluble fractalkine in patients with mild cognitive impairment and Alzheimer’s disease. Neurosci Lett 436:196–200CrossRefGoogle Scholar
  78. 78.
    Bhaskar K et al (2010) Regulation of tau pathology by the microglial fractalkine receptor. Neuron 68:19–31CrossRefGoogle Scholar
  79. 79.
    Heneka MT et al (2010) Locus ceruleus controls Alzheimer’s disease pathology by modulating microglial functions through norepinephrine. Proc Natl Acad Sci U S A 107:6058–6063CrossRefGoogle Scholar
  80. 80.
    Martorell AJ et al (2019) Multi-sensory gamma stimulation ameliorates alzheimer’s-associated pathology and improves cognition. Cell 177:256–271.e22CrossRefGoogle Scholar

Copyright information

© Springer Medizin Verlag GmbH, ein Teil von Springer Nature 2019

Authors and Affiliations

  • Sergio Castro-Gomez
    • 1
  • Julius Binder
    • 1
  • Michael T. Heneka
    • 1
    • 2
    Email author
  1. 1.Klinik für Neurodegenerative Erkrankungen und GerontopsychiatrieUniversitätsklinikum Bonn (AöR)BonnDeutschland
  2. 2.Deutsches Zentrum für Neurodegenerative ErkrankungenBonnDeutschland

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