Cerebral immune system; Dementia; Genetic risk factors; Microglia; Neurodegeneration; Disease Progression; Genome-Wide Association Study; Humans; Alzheimer Disease/genetics; Alzheimer Disease/immunology; Immunity, Innate; Inflammation; Microglia/immunology; Alzheimer Disease; Neurology; Neurology (clinical); Psychiatry and Mental Health; General Medicine
Abstract :
[en] 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.
Disciplines :
Neurology
Author, co-author :
Castro-Gomez, Sergio; Klinik für Neurodegenerative Erkrankungen und Gerontopsychiatrie, Universitätsklinikum Bonn (AöR), Sigmund-Freud-Str. 25, Venusberg-Campus 1, Gebäude 80, 53127, Bonn, Deutschland
Binder, Julius; Klinik für Neurodegenerative Erkrankungen und Gerontopsychiatrie, Universitätsklinikum Bonn (AöR), Sigmund-Freud-Str. 25, Venusberg-Campus 1, Gebäude 80, 53127, Bonn, Deutschland
HENEKA, Michael ; Klinik für Neurodegenerative Erkrankungen und Gerontopsychiatrie, Universitätsklinikum Bonn (AöR), Sigmund-Freud-Str. 25, Venusberg-Campus 1, Gebäude 80, 53127, Bonn, Deutschland. michael.heneka@ukb.uni-bonn.de ; Deutsches Zentrum für Neurodegenerative Erkrankungen, Bonn, Deutschland. michael.heneka@ukb.uni-bonn.de
External co-authors :
yes
Language :
German
Title :
Neuroinflammation als Motor der Alzheimer-Erkrankung.
Alternative titles :
[en] Neuroinflammation as motor of Alzheimer's disease.
Medzhitov R (2008) Origin and physiological roles of inflammation. Nature 454:428–435
Kierdorf K et al (2013) Microglia emerge from erythromyeloid precursors via Pu.1-and Irf8-dependent pathways. Nat Neurosci 16:273–280
Askew K et al (2017) Coupled proliferation and Apoptosis maintain the rapid turnover of Microglia in the adult brain. Cell Rep 18:391–405
Benarroch EE (2013) Microglia: Multiple roles in surveillance, circuit shaping, and response to injury. Baillieres Clin Neurol 81:1079–1088
Pierre WC et al (2017) Neonatal microglia: the cornerstone of brain fate. Brain Behav Immun 59:333–345
Parkhurst CN et al (2013) Microglia promote learning-dependent synapse formation through brain-derived neurotrophic factor. Cell 155:1596–1609
Querfurth HW, LaFerla FM (2010) Alzheimer’s disease. N Engl J Med 362:329–344
Stelzmann RA, Schnitzlein HN, Murtagh FR (1995) VIEWPOINT an English translation of alzheimer’s 1907 paper „Über eine eigenartige Erkrankung der Hirnrinde“. Clin Anat 8:429–443
Heneka MT et al (2015) Neuroinflammation in Alzheimer’s disease. Lancet Neurol 14:388–405
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 44:385–396
I. TJ, E. EW, S. DM, L. KM (2010) Long-term cognitive impairment and functional disability among survivors of severe sepsis. JAMA 304:1787–1794
Scarmeas N et al (2009) Physical activity, diet, and risk of Alzheimer disease. JAMA 302:627–637
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. 10.1089/neu.2018.6346
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) 75:391–398
Zeineh MM et al (2015) Activated iron-containing microglia in the human hippocampus identified by magnetic resonance imaging in Alzheimer disease. Neurobiol Aging 36:2483–2500
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 35:306–328
Kreisl WC et al (2013) In vivo radioligand binding to translocator protein correlates with severity of Alzheimer’s disease. Brain 136:2228–2238
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. 10.1093/brain/aww017
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 51:414–430
Jansen IE et al (2019) Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer’s disease risk. Nat Genet 51:404–413
Lambert JC et al (2013) Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease. Nat Genet 45:1452–1458
Huang K et al (2017) A common haplotype lowers PU.1 expression in myeloid cells and delays onset of Alzheimer’s disease. Nat Neurosci 20:1052–1061
Guerreiro R et al (2013) TREM2 variants in Alzheimer’s disease. N Engl J Med 368:117–127
Jonsson T et al (2013) Variant of TREM2 associated with the risk of Alzheimer’s disease. N Engl J Med 368:107–116
Wang S, Colonna M (2019) Microglia in Alzheimer’s disease: A target for immunotherapy. J Leukoc Biol:1–9. 10.1002/JLB.MR0818-319R
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. 10.1038/ng.3916
Huang Y, Weisgraber KH, Mucke L, Mahley RW (2004) Apolipoprotein E. J Mol Neurosci 23:189–204
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.e1
Krasemann S et al (2017) The TREM2-APOE pathway drives the Transcriptional phenotype of dysfunctional Microglia in Neurodegenerative diseases. Immunity 47:566–581.e9
Mathys H et al (2019) Single-cell transcriptomic analysis of Alzheimer’s disease. Nature. 10.1038/s41586-019-1195-2
Dickson DW et al (1988) Alzheimer’s disease. A double-labeling immunohistochemical study of senile plaques. Am J Pathol 132:86–101
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 16:27–38
Du Yan S et al (1996) RAGE and amyloid-β peptide neurotoxicity in Alzheimer’s disease. Nature 382:685–691
Landreth GE, Reed-geaghan EG (2009) Toll-like receptors: roles in infection and neuropathology Bd. 336. Springer, Berlin Heidelberg
El Khoury J et al (1996) Scavenger receptor-mediated adhesion of microglia to β‑amyloid fibrils. Nature 382:716–719
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 23:2665–2674
Halle A et al (2008) The NALP3 inflammasome is involved in the innate immune response to amyloid-β. Nat Immunol 9:857–865
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 14:812–820
Venegas C et al (2017) Microglia-derived ASC specks cross-seed amyloid-β in Alzheimer’s disease. Nature 552:355–361
Asai H et al (2015) Depletion of microglia and inhibition of exosome synthesis halt tau propagation. Nat Neurosci 18:1584–1593
Liddelow SA et al (2017) Neurotoxic reactive astrocytes are induced by activated microglia. Nature 541:481–487
Bisht K et al (2016) Dark microglia: a new phenotype predominantly associated with pathological states. Glia 64:826–839
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 20:1371–1376
Olmos-Alonso A et al (2016) Pharmacological targeting of CSF1R inhibits microglial proliferation and prevents the progression of Alzheimer’s-like pathology. Brain 139:891–907
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 60:615–629
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 453:41–44
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. 10.1186/1742-2094-8-92
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 30:15369–15373
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 10:1–5
Harold D et al (2009) Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer’s disease. Nat Genet 41:1088–1093
Lambert JC et al (2009) Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer’s disease. Nat Genet 41:1094–1099
Hong S et al (2016) Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science 80(352):712–716
Yin C et al (2019) ApoE attenuates unresolvable inflammation by complex formation with activated C1q. Nat Med 25:496–506
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 72:233–238
Ghosh S et al (2013) Sustained Interleukin-1 Overexpression exacerbates tau pathology despite reduced Amyloid burden in an alzheimer’s mouse model. J Neurosci 33:5053–5064
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 24:548–559
Chakrabarty P et al (2010) IFN- promotes complement expression and attenuates Amyloid plaque deposition in Amyloid precursor protein Transgenic mice. J Immunol 184:5333–5343
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 179:2053–2070
Vom Berg J et al (2012) Inhibition of IL-12/IL-23 signaling reduces Alzheimer’s diseasea-like pathology and cognitive decline. Nat Med 18:1812–1819
Zetterberg H, Andreasen N, Blennow K (2004) Increased cerebrospinal fluid levels of transforming growth factor-β1 in Alzheimer’s disease. Neurosci Lett 367:194–196
Tesseur I et al (2006) Deficiency in neuronal TGF-β signaling promotes neurodegeneration and Alzheimer’s pathology. J Clin Invest 116:3060–3069
Chakrabarty P et al (2015) IL-10 alters Immunoproteostasis in APP mice, increasing plaque burden and worsening cognitive behavior. Neuron 85:519–533
Ulland TK, Colonna M (2018) TREM2—a key player in microglial biology and Alzheimer disease. Nat Rev Neurol 14:667–675
Hsieh CL et al (2009) A role for TREM2 ligands in the phagocytosis of apoptotic neuronal cells by microglia. J Neurochem 109:1144–1156
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. 10.15252/emmm.201506123
Gurvit H et al (2014) TREM2 mutations implicated in neurodegeneration impair cell surface transport and phagocytosis. Sci Transl Med 6:243ra86–243ra86
Ulland TK et al (2017) TREM2 maintains mcroglial metabolic fitness in alzheimer’s disease. Cell 170:649–663.e13
Wang Y et al (2014) Altered microglial response to Aβ plaques in APPPS1-21 mice heterozygous for TREM2. Mol Neurodegener 9:20. 10.1186/1750-1326-9-20
Mazaheri F et al (2017) TREM2 deficiency impairs chemotaxis and microglial responses to neuronal injury. Embo Rep 18:1186–1198
Song WM et al (2018) Humanized TREM2 mice reveal microglia-intrinsic and -extrinsic effects of R47H polymorphism. J Exp Med 215:745–760
Jiang T et al (2015) Silencing of TREM2 exacerbates tau pathology, neurodegenerative changes, and spatial learning deficits in P301S tau transgenic mice. Neurobiol Aging 36:3176–3186
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 215:1627–1647
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–E1325
Katsimpardi L et al (2014) Vascular and Neurogenic rejuvenation of the aging mouse brain by young systemic factors. Science 80(344):630–634
Domercq M, Vazquez-Villoldo N, Matute C (2013) Neurotransmitter signaling in the pathophysiology of microglia. Front Cell Neurosci 7:1–17
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 436:196–200
Bhaskar K et al (2010) Regulation of tau pathology by the microglial fractalkine receptor. Neuron 68:19–31
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 107:6058–6063
Martorell AJ et al (2019) Multi-sensory gamma stimulation ameliorates alzheimer’s-associated pathology and improves cognition. Cell 177:256–271.e22
