[en] Alzheimer's disease (AD) is characterized by amyloid beta (Aβ) accumulation, tau pathology and neuroinflammation. Recently, there has been considerable interest in the role of neuroinflammation in directly contributing to the progression of AD. Studies in mice and humans have identified a role for microglial cells, the resident innate immune cells of the central nervous system, in AD. Activated microglia are a key hallmark of the disease and the secretion of proinflammatory cytokines by microglia may result in a positive feedback loop between neurons and microglia, resulting in ongoing low-grade inflammation. Traditionally, the pathways of Aβ production and neuroinflammation have been considered independently; however, recent studies suggest that these processes may converge to promote the pathology associated with AD. Here we review the importance of inflammation and microglia in AD development and effects of inflammatory responses on cellular pathways of neurons, including Aβ generation.
Disciplines :
Neurology
Author, co-author :
Webers, Alessandra; Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, VIC, Australia ; Department of Neurodegenerative Disease and Geriatric Psychiatry, University of Bonn, Bonn, Germany
HENEKA, Michael ; Department of Neurodegenerative Disease and Geriatric Psychiatry, University of Bonn, Bonn, Germany ; German Center for Neurodegenerative Diseases, Bonn, Germany
Gleeson, Paul A; Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, VIC, Australia
External co-authors :
yes
Language :
English
Title :
The role of innate immune responses and neuroinflammation in amyloid accumulation and progression of Alzheimer's disease.
Alzheimer A. Ueber einen eigenartigen schweren Erkrankungsprozess der Hirnrinde. Neurol Central 1906; 25: 1134.
Probst A, Langui D, Ulrich J. Alzheimer's disease: a description of the structural lesions. Brain Pathol; 1: 229–239.
Ginhoux F, Greter M, Leboeuf M, et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 2010; 330: 841–845.
Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 1991; 82: 239–259.
Heneka MT, Kummer MP, Latz E. Innate immune activation in neurodegenerative disease. Nat Rev Immunol 2014; 14: 463–477.
Hong S, Dissing-Olesen L, Stevens B. New insights on the role of microglia in synaptic pruning in health and disease. Curr Opin Neurobiol 2016; 36: 128–134.
Block ML, Hong J-S. Chronic microglial activation and progressive dopaminergic neurotoxicity. Biochem Soc Trans 2007; 35: 1127–1132.
Kang J, Lemaire H-G, Unterbeck A, et al. The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor. Nature 1987; 325: 733.
Vetrivel KS, Thinakaran G. Membrane rafts in Alzheimer's disease beta-amyloid production. Biochim et Biophys Acta (BBA) - Mol Cell Biol Lipids 2010; 1801: 860–867.
Toh WH, Chia PZC, Hossain MI, Gleeson PA. GGA1 regulates signal-dependent sorting of BACE1 to recycling endosomes, which moderates Aβ production. MBoC 2018; 29: 191–208.
Sisodia SS. Beta-amyloid precursor protein cleavage by a membrane-bound protease. PNAS 1992; 89: 6075–6079.
Thinakaran G, Koo EH. Amyloid precursor protein trafficking, processing, and function. J Biol Chem 2008; 283: 29615–29619.
Wang X, Zhou X, Li G, Zhang Y, Wu Y, Song W. Modifications and trafficking of APP in the pathogenesis of Alzheimer's disease. Front Mol Neurosci 2017; 10: 294. https://doi.org/10.3389/fnmol.2017.00294.
Tan JZA, Gleeson PA. The role of membrane trafficking in the processing of amyloid precursor protein and production of amyloid peptides in Alzheimer's disease. Biochim Biophys Acta (BBA) -Biomembr 2019; 1861: 697–712.
Rajendran L, Annaert W. Membrane trafficking pathways in Alzheimer's disease. Traffic 2012; 13: 759–770.
Haass C. Take five—BACE and the γ-secretase quartet conduct Alzheimer's amyloid β-peptide generation. EMBO J 2004; 23: 483–488.
Fukumoto H, Cheung BS, Hyman BT, Irizarry MC. β-secretase protein and activity are increased in the neocortex in Alzheimer disease. Arch Neurol 2002; 59: 1381–1389.
Vassar R, Kovacs DM, Yan R, Wong PC. The β-secretase enzyme BACE in health and Alzheimer's disease: regulation, cell biology, function, and therapeutic potential. J Neurosci 2009; 29: 12787–12794.
Yan R, Han P, Miao H, Greengard P, Xu H. The transmembrane domain of the Alzheimer's β-secretase (BACE1) determines its late Golgi localization and access to APP substrate. J Biol Chem 2009; 276: 36788–36796.
Laird FM, Cai H, Savonenko AV, et al. BACE1, a major determinant of selective vulnerability of the brain to amyloid-beta amyloidogenesis, is essential for cognitive, emotional, and synaptic functions. J Neurosci 2005; 25: 11693–11709.
Coimbra JRM, Marques DFF, Baptista SJ, et al. Highlights in BACE1 inhibitors for Alzheimer's disease treatment. Front Chem 2018; 6: 178. https://doi.org/10.3389/fchem.2018.00178
Müller UC, Deller T, Korte M. Not just amyloid: physiological functions of the amyloid precursor protein family. Nat Rev Neurosci 2017; 18: 281–298.
Gosztyla ML, Brothers HM, Robinson SR. Alzheimer's amyloid-β is an antimicrobial peptide: a review of the evidence. J Alzheimer's Dis 2018; 62: 1495–1506.
Scheuner D, Eckman C, Jensen M, et al. Secreted amyloid β–protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease. Nat Med 1996; 2: 864.
Weggen S, Beher D. Molecular consequences of amyloid precursor protein and presenilin mutations causing autosomal-dominant Alzheimer's disease. Alzheimer's Res Ther 2012; 4: 9.
Jonsson T, Atwal JK, Steinberg S, et al. A mutation in APP protects against Alzheimer's disease and age-related cognitive decline. Nature 2012; 488: 96–99.
Vassar R, Bennett BD, Babu-Khan S, et al. Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE. Science 1999; 286: 735–741.
Jarrett JT, Berger EP, Lansbury PT. The C-terminus of the β protein is critical in amyloidogenesisa. Ann N Y Acad Sci 1993; 695: 144–148.
Tarasoff-Conway JM, Carare RO, Osorio RS, et al. Clearance systems in the brain—implications for Alzheimer disease. Nat Rev Neurol 2015; 11: 457–470.
Takemura R, Okabe S, Umeyama T, Kanai Y, Cowan NJ, Hirokawa N. Increased microtubule stability and alpha tubulin acetylation in cells transfected with microtubule-associated proteins MAP1B, MAP2 or tau. J Cell Sci 1992; 103: 953–964.
Iba M, Guo JL, McBride JD, Zhang B, Trojanowski JQ, Lee VM-Y. Synthetic tau fibrils mediate transmission of neurofibrillary tangles in a transgenic mouse model of Alzheimer's-like tauopathy. J Neurosci 2013; 33: 1024–1037.
Crimins JL, Pooler A, Polydoro M, Luebke JI, Spires-Jones TL. The intersection of amyloid β and tau in glutamatergic synaptic dysfunction and collapse in Alzheimer's disease. Ageing Res Rev 2013; 12: 757–763.
Bussian TJ, Aziz A, Meyer CF, Swenson BL, van Deursen JM, Baker DJ. Clearance of senescent glial cells prevents tau-dependent pathology and cognitive decline. Nature 2018; 562: 578–582.
del Rio-Hortega P. Microglia. Cytol Cell Pathol Nerv Syst 1932; 11: 481–534.
Colonna M, Butovsky O. Microglia function in the central nervous system during health and neurodegeneration. Annu Rev Immunol 2017; 35: 441–468.
Kierdorf K, Erny D, Goldmann T, et al. Microglia emerge from erythromyeloid precursors via Pu.1- and Irf8-dependent pathways. Nat Neurosci 2013; 16: 273–280.
Prinz M, Priller J. Microglia and brain macrophages in the molecular age: from origin to neuropsychiatric disease. Nat Rev Neurosci 2014; 15: 300–312.
Hammond TR, Robinton D, Stevens B. Microglia and the brain: complementary partners in development and disease. Annu Rev Cell Dev Biol 2018; 34: 523–544.
Färber K, Kettenmann H. Physiology of microglial cells. Brain Res Rev 2005; 48: 133–143.
Roy A, Fung YK, Liu X, Pahan K. Up-regulation of microglial CD11b expression by nitric oxide. J Biol Chem 2006; 281: 14971–14980.
Nakajima K, Kohsaka S. Microglia: activation and their significance in the central nervous system. J Biochem 2001; 130: 169–175.
Zhao H, Cheng L, Liu Y, et al. Mechanisms of anti-inflammatory property of conserved dopamine neurotrophic factor: inhibition of jnk signaling in lipopolysaccharide-induced microglia. J Mol Neurosci 2014; 52: 186–192.
Nakajima K, Kikuchi Y, Ikoma E, et al. Neurotrophins regulate the function of cultured microglia. Glia 1998; 24: 272–289.
Lee DC, Rizer J, Selenica M-LB, et al. LPS- induced inflammation exacerbates phospho-tau pathology in rTg4510 mice. J Neuroinflamm 2010; 7: 56.
Ransohoff RM. A polarizing question: do M1 and M2 microglia exist? Nat Neurosci 2016; 19: 987–991.
Hanisch U-K. Functional diversity of microglia – how heterogeneous are they to begin with? Front Cell Neurosci 2013; 7: 65. https://doi.org/10.3389/fncel.2013.00065.
Nimmerjahn A, Kirchhoff F, Helmchen F. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 2005; 308: 1314–1318.
Lee CYD, Landreth GE. The role of microglia in amyloid clearance from the AD brain. J Neural Transm 2010; 117: 949–960.
Heneka MT, Carson MJ, El Khoury J, et al. Neuroinflammation in Alzheimer's disease. Lancet Neurol 2015; 14: 388–405.
Heneka MT, Kummer MP, Stutz A, et al. NLRP3 is activated in Alzheimer's disease and contributes to pathology in APP/PS1 mice. Nature 2013; 493: 674–678.
Fiebich BL, Batista CRA, Saliba SW, Yousif NM, de Oliveira ACP. Role of microglia TLRs in neurodegeneration. Front Cell Neurosci 2018; 12: 329. https://doi.org/10.3389/fncel.2018.00329.
Fonseca MI, Chu S-H, Hernandez MX, et al. Cell-specific deletion of C1qa identifies microglia as the dominant source of C1q in mouse brain. J Neuroinflammation 2017; 14: 48. https://doi.org/10.1186/s12974-017-0814-9.
Liddelow SA, Guttenplan KA, Clarke LE, et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature 2017; 541: 481–487.
Walsh JG, Muruve DA, Power C. Inflammasomes in the CNS. Nat Rev Neurosci 2014; 15: 84–97.
Venegas C, Kumar S, Franklin BS, et al. Microglia-derived ASC specks cross-seed amyloid-β in Alzheimer's disease. Nature 2017; 552: 355–361.
Frautschy SA, Yang F, Irrizarry M, et al. Microglial response to amyloid plaques in APPsw transgenic mice. Am J Pathol 1998; 152: 307–317.
McGeer PL, Itagaki S, Tago H, McGeer EG. Reactive microglia in patients with senile dementia of the Alzheimer type are positive for the histocompatibility glycoprotein HLA-DR. Neurosci Lett 1987; 79: 195–200.
Allen NJ. Astrocyte regulation of synaptic behavior. Annu Rev Cell Dev Biol 2014; 30: 439–463.
Lian H, Yang L, Cole A, et al. NFκB-activated astroglial release of complement C3 compromises neuronal morphology and function associated with Alzheimer's disease. Neuron 2015; 85: 101–115.
Qin Y, Garrison BS, Ma W, et al. A milieu molecule for TGF-β required for microglia function in the nervous system. Cell 2018; 174: 156–171.e16
Kim YS, Jung HM, Yoon B-E. Exploring glia to better understand Alzheimer's disease. Animal Cells Syst 2018; 22: 213–218.
Frost GR, Li Y-M. The role of astrocytes in amyloid production and Alzheimer's disease. Open Biol 2017; 7: 170228. https://doi.org/10.1098/rsob.170228.
Boillée S, Yamanaka K, Lobsiger CS, et al. Onset and progression in inherited ALS determined by motor neurons and microglia. Science 2006; 312: 1389–1392.
El Khoury JB, Moore KJ, Means TK, et al. CD36 mediates the innate host response to beta-amyloid. J Exp Med 2003; 197: 1657–1666.
Grammas P, Ovase R. Inflammatory factors are elevated in brain microvessels in Alzheimer's disease. Neurobiol Aging 2001; 22: 837–842.
Shohami E, Ginis I, Hallenbeck JM. Dual role of tumor necrosis factor alpha in brain injury. Cytokine Growth Factor Rev 1999; 10: 119–130.
Chakrabarty P, Herring A, Ceballos-Diaz C, Das P, Golde TE. Hippocampal expression of murine TNFα results in attenuation of amyloid deposition in vivo. Mol Neurodegener 2011; 6: 16.
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 2016; 5: 7. https://doi.org/10.1186/s40035-016-0054-4.
Ye L, Huang Y, Zhao L, et al. IL-1β and TNF-α induce neurotoxicity through glutamate production: a potential role for neuronal glutaminase. J Neurochem 2013; 125: 897–908.
Colton CA, Mott RT, Sharpe H, Xu Q, Van Nostrand WE, Vitek MP. Expression profiles for macrophage alternative activation genes in AD and in mouse models of AD. J Neuroinflammation 2006; 3: 27.
Orsini F, De Blasio D, Zangari R, Zanier ER, De Simoni M-G. Versatility of the complement system in neuroinflammation, neurodegeneration and brain homeostasis. Front Cell Neurosci 2014; 8: 380. https://doi.org/10.3389/fncel.2014.00380.
Eikelenboom P, Hack CE, Rozemuller JM, Stam FC. Complement activation in amyloid plaques in Alzheimer's dementia. Virchows Arch B 1989; 56: 259–262.
Lee JW, Lee YK, Yuk DY, et al. Neuro-inflammation induced by lipopolysaccharide causes cognitive impairment through enhancement of beta-amyloid generation. J Neuroinflammation 2008; 5: 37.
Heneka MT. Inflammasome activation and innate immunity in Alzheimer's disease. Brain Pathol 2017; 27: 220–222.
Jansen IE, Savage JE, Watanabe K, et al. Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer's disease risk. Nat Genet 2019; 51: 404.
Lambert J-C, Ibrahim-Verbaas CA, Harold DC, et al. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease. Nat Genet 2013; 45: 1452–1458.
Lambert J-C, Heath S, Even G, et al. Genome-wide association study identifies variants at CLU and CR81 associated with Alzheimer's disease. Nat Genet 2009; 41: 1094–1099.
Bettens K, Sleegers K, Van Broeckhoven C. Genetic insights in Alzheimer's disease. Lancet Neurol 2013; 12: 92–104.
Jay TR, Miller CM, Cheng PJ, et al. TREM2 deficiency eliminates TREM2 + inflammatory macrophages and ameliorates pathology in Alzheimer's disease mouse models. J Exp Med 2015; 212: 287–295.
Schlepckow K, Kleinberger G, An Fukumori A, et al. Alzheimer-associated TREM2 variant occurs at the ADAM cleavage site and affects shedding and phagocytic function. EMBO Mol Med 2017; 9: 1356–1365. e201707672.
Lee CYD, Daggett A, Gu X, et al. Elevated TREM2 gene dosage reprograms microglia responsivity and ameliorates pathological phenotypes in Alzheimer's disease models. Neuron 2018; 97: 1032–1048.e5.
Ulland TK, Song WM, Huang SC-C, et al. TREM2 maintains microglial metabolic fitness in Alzheimer's disease. Cell 2017; 170: 649–663.e13.
Ulland TK, Colonna M. TREM2 — a key player in microglial biology and Alzheimer disease. Nat Rev Neurol 2018; 14: 667–675.
Song WM, Joshita S, Zhou Y, Ulland TK, Gilfillan S, Colonna M. Humanized TREM2 mice reveal microglia-intrinsic and -extrinsic effects of R47H polymorphism. J Exp Med 2018; 215: 745–760.
Griciuc A, Serrano-Pozo A, Parrado AR, et al. Alzheimer's disease risk gene CD33 inhibits microglial uptake of amyloid beta. Neuron 2013; 78: 631–643.
Alasmari F, Alshammari MA, Alasmari AF, Alanazi WA, Alhazzani K. Neuroinflammatory cytokines induce amyloid beta neurotoxicity through modulating amyloid precursor protein levels/metabolism. Biomed Res Int 2018; 78: 3087475. https://doi.org/10.1155/2018/3087475.
Sastre M, Walter J, Gentleman SM. Interactions between APP secretases and inflammatory mediators. J Neuroinflammation 2008; 5: 25.
Zhu K, Peters F, Filser S, Herms J. Consequences of pharmacological BACE inhibition on synaptic structure and function. Biol Psychiat 2018; 84: 478–487.
Zhu B-L, Long Y, Luo W, et al. MMP13 inhibition rescues cognitive decline in Alzheimer transgenic mice via BACE1 regulation. Brain 2019; 142: 176–192.
Small SA, Simoes-Spassov S, Mayeux R, Petsko GA. Endosomal traffic jams represent a pathogenic hub and therapeutic target in Alzheimer's disease. Trends Neurosci 2017; 40: 592–602.
Kamenetz F, Tomita T, Hsieh H, et al. APP processing and synaptic function. Neuron 2003; 37: 925–937.
Cirrito JR, Kang J-E, Lee J, et al. Endocytosis is required for synaptic activity-dependent release of amyloid-β in vivo. Neuron 2008; 58: 42–51.
Das U, Scott DA, Ganguly A, Koo EH, Tang Y, Roy S. Activity-induced convergence of APP and BACE-1 in acidic microdomains via an endocytosis-dependent pathway. Neuron 2013; 79: 447–460.
Yamamoto M, Kiyota T, Horiba M, et al. Interferon-γ and tumor necrosis factor-α regulate amyloid-β plaque deposition and β-secretase expression in swedish mutant APP transgenic mice. Am J Pathol 2007; 170: 680–692.
Jang J-H, Surh Y-J. β-Amyloid-induced apoptosis is associated with cyclooxygenase-2 up-regulation via the mitogen-activated protein kinase–NF-κB signaling pathway. Free Radic Biol Med 2005; 38: 1604–1613.
Tao Q, Ang TFA, DeCarli C, et al. Association of chronic low-grade inflammation with risk of Alzheimer disease in ApoE4 carriers. JAMA Netw Open 2018; 1: e183597.
Teixeira FB, Saito MT, Matheus FC, et al. Periodontitis and Alzheimer's disease: a possible comorbidity between oral chronic inflammatory condition and neuroinflammation. Front Aging Neurosci 2017; 9: 327. https://doi.org/10.3389/fnagi.2017.00327.
Chou RC, Kane M, Ghimire S, Gautam S, Gui J. Treatment for rheumatoid arthritis and risk of Alzheimer's disease: a nested case-control analysis. CNS Drugs 2016; 30: 1111–1120.
Kao L-T, Kang J-H, Lin H-C, Huang C-C, Lee H-C, Chung S-D. Rheumatoid arthritis was negatively associated with Alzheimer's disease: a population-based case-control study. PLoS One 2016; 11: e0168106.
Gómez-Isla T, Blesa R, Boada M, et al. A randomized, double-blind, placebo controlled-trial of triflusal in mild cognitive impairment: the TRIMCI study. Alzheimer Dis Assoc Disord 2008; 22: 21–29.
Rogers J, Kirby LC, Hempelman SR, et al. Clinical trial of indomethacin in Alzheimer's disease. Neurology 1993; 43: 1609–1611.
Imbimbo BP, Solfrizzi V, Panza F. Are NSAIDs useful to treat Alzheimer's disease or mild cognitive impairment? Front Aging Neurosci 2010; 2. https://doi.org/10.3389/fnagi.2010.00019.
Schlaak JF, Schwarting A, Knolle P, Meyer zum Büschenfelde KH, Mayet W. Effects of Th1 and Th2 cytokines on cytokine production and ICAM-1 expression on synovial fibroblasts. Ann Rheum Dis 1995; 54: 560–565.
Wang M, Sampson ER, Jin H, et al. MMP13 is a critical target gene during the progression of osteoarthritis. Arthritis Res Ther 2013; 15: R5.
Paumier J-M, Thinakaran G. Matrix metalloproteinase 13, a new target for therapy in Alzheimer's disease. Genes Dis 2019; 6: 1–2.
Cho HJ, Verbridge SS, Davalos RV, Lee YW. Development of an in vitro 3D brain tissue model mimicking in vivo-like pro-inflammatory and pro-oxidative responses. Ann Biomed Eng 2018; 46: 877–887.
Croxford AL, Buch T. Cytokine reporter mice in immunological research: perspectives and lessons learned. Immunology 2011; 132: 1–8.
MacDonald ML, Favo D, Garver M, et al. Laser capture microdissection–targeted mass spectrometry: a method for multiplexed protein quantification within individual layers of the cerebral cortex. Neuropsychopharmacology 2019; 44: 743.
Corder EH, Saunders AM, Strittmatter WJ, et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science 1993; 261: 921–923.