小胶质细胞对阿尔兹海默病发生发展的影响作用

doi:10.12034/j.issn.1009-606X.218206

摘要/Abstract

摘要： 阿尔兹海默病(老年性痴呆，AD)是由β淀粉样蛋白(Aβ)和微管相关蛋白(Tau)聚集形成的具有毒性作用的寡聚物而引起的老年人主要以记忆力下降和脑部形成老年斑、神经纤维缠绕为特征的神经退行性疾病. 小胶质细胞作为中枢神经系统中的固有免疫细胞，是脑内免疫监视的关键成分，发挥内源性免疫防御作用. 正常生理状态的小胶质细胞能有效吞噬和清除毒性Aβ寡聚体，阻止AD发生. 在AD病理过程中，过度激活的小胶质细胞通过补体依赖途径过度吞噬突触，导致突触丧失，同时大量释放炎症因子，促进Tau相关病理变化，对神经元造成直接损伤，导致认知功能下降. 由此可见，小胶质细胞在AD发生发展过程中起着双刃剑的作用，探明小胶质细胞的极化状态及其在AD疾病机理中的作用将为攻克AD的药物研发提供突破性思路.

关键词: 小胶质细胞, 阿尔兹海默病, β淀粉样蛋白, 突触, 神经炎症

Abstract: Microglia, the innate immune cells of the central nervous system (CNS), serve as resident phagocytes that dynamically survey the environment and play crucial roles in CNS health and disease. Various roles are emerging for microglia in the healthy brain, from sculpting developing neuronal circuits to guiding neural plasticity. Understanding the physiological functions of microglia is important to evaluate their roles in disease. At pathological state, conditions associated with loss of cerebral homeostasis induce several dynamic microglial processes, including changes of cellular morphology, surface phenotype, secretory inflammatory mediators and proliferative responses, termed as an “activated state”. Activation and proliferation of microglia in the brain represents a prominent feature of several neurodegenerative diseases including Alzheimer's disease (AD). AD is a progressive neurodegenerative disorder that is the most common cause of dementia, which is defined as a significant, persistent, and progressive memory loss combined with cognitive impairment and personality change. The key features of AD pathology are amyloid plaques by extracellular accumulation of amyloid-β (Aβ) and intracellular neurofibrillary tangles composed of tau proteins. There is mounting evidence that microglia protect against the incidence of AD, as impaired microglial activities and altered microglial responses to Aβ are associated with increased AD risk. In CNS, microglia have protective functions by phagocytosis and clearance of toxic Aβ oligomers, which prevent the development of AD. Once activated, microglia can mediate synapse loss by engulfment of synapses via a complement-dependent mechanism, secrete inflammatory factors and exacerbate tau pathology, resulting in the neuron injury and cognitive deficits. Therefore, microglia show the double-edged sword function in AD pathogenesis. Understanding the multiple states of microglial activation and their roles in AD pathology will provide breakthrough ideas for developing AD therapeutic strategies. In this review, the role of microglia in the pathogenesis of AD and the modulation of microglia activity as a therapeutic potential will be discussed.

Key words: Microglia, Alzheimer's disease, amyloid-β, synapse, Neuroinflammation

刘小歌张伦于晓琳. 小胶质细胞对阿尔兹海默病发生发展的影响作用[J]. 过程工程学报, 2018, 18(5): 900-907.

Xiaoge LIU Lun ZHANG Xiaolin YU. The role of microglia in Alzheimer's disease[J]. Chin. J. Process Eng., 2018, 18(5): 900-907.

参考文献

[1]Scheltens P, Blennow K, Breteler M M, et al.Alzheimer's disease[J].Lancet, 2016, 388(10043):505-517
[2]Frisoni G B, Boccardi M, Barkhof F, et al.Strategic roadmap for an early diagnosis of Alzheimer's disease based on biomarkers[J].Lancet Neurol, 2017, 16(8):661-676
[3]Castellani R J, Perry G.Pathogenesis and disease-modifying therapy in Alzheimer's disease: the flat line of progress[J].Arch Med Res, 2012, 43(8):694-698
[4]Lane C A, Hardy J, Schott J M.Alzheimer's disease[J].Eur J Neurol, 2018, 25(1):59-70
[5]Alzheimer' s A.Alzheimer's disease facts and figures[J].Alzheimers Dement, 2016, 12(4):459-509
[6]Villemagne V L, Dore V, Burnham S C, et al.Imaging tau and amyloid-beta proteinopathies in Alzheimer disease and other conditions[J].Nat Rev Neurol, 2018, 14(4):225-236
[7]Kalia L V, Lang A E.Parkinson's disease[J].Lancet, 2015, 386(9996):896-912
[8]Goedert M, Spillantini M G, Del Tredici K, et al.years of Lewy pathology[J].Nat Rev Neurol, 2013, 9(1):13-24
[9]Grima J C, Daigle J G, Arbez N, et al.Mutant Huntingtin Disrupts the Nuclear Pore Complex[J].Neuron, 2017, 94(1):93-107
[10]Aguzzi A, Falsig J.Prion propagation,toxicity and degradation[J].Nat Neurosci, 2012, 15(7):936-939
[11]Knowles T P, Vendruscolo M, Dobson C M.The amyloid state and its association with protein misfolding diseases[J].Nat Rev Mol Cell Biol, 2014, 15(6):384-396
[12]Dobson C M.Protein folding and misfolding[J].Nature, 2003, 426(6968):884-890
[13]Chiti F, Dobson C M.Protein misfolding, functional amyloid, and human disease.[J].Annu Rev Biochem, 2006, 75(75):333-366
[14]Guerrero-Munoz M J, Castillo-Carranza D L, Kayed R.Therapeutic approaches against common structural features of toxic oligomers shared by multiple amyloidogenic proteins[J].Biochem Pharmacol, 2014, 88(4):468-478
[15]Kayed R, Lasagna-Reeves C A.Molecular mechanisms of amyloid oligomers toxicity [J].J Alzheimers Dis, 2013, 33 ( Suppl 1):S67-S78
[16]Kayed R, Head E, Thompson J L, et al.Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis[J].Science, 2003, 300(5618):486-489
[17]Tay T L, Savage J C, Hui C W, et al.Microglia across the lifespan: from origin to function in brain development,plasticity and cognition[J].J Physiol, 2017, 595(6):1929-1945
[18]Salter M W, Beggs S.Sublime microglia: expanding roles for the guardians of the CNS[J].Cell, 2014, 158(1):15-24
[19]Colonna M, Butovsky O.Microglia Function in the Central Nervous System During Health and Neurodegeneration[J].Annu Rev Immunol, 2017, 35(35):441-468
[20]Salter M W, Stevens B.Microglia emerge as central players in brain disease[J].Nat Med, 2017, 23(9):1018-1027
[21]Vilhardt F.Microglia: phagocyte and glia cell[J].Int J Biochem Cell Biol, 2005, 37(1):17-21
[22]Koeglsperger T, Li S, Brenneis C, et al.Impaired glutamate recycling and GluN2B-mediated neuronal calcium overload in mice lacking TGF-beta1 in the CNS[J].Glia, 2013, 61(6):985-1002
[23]Mills C D.M1 and M2 Macrophages: Oracles of Health and Disease[J].Critical Reviews in Immunology, 2012, 32(06):463-488
[24]Salter M W, Stevens B.Microglia emerge as central players in brain disease[J].Nature Medicine, 2017, 23(9):1018-1027
[25]Hansen D V, Hanson J E, Sheng M.Microglia in Alzheimer's disease[J].J Cell Biol, 2018, 217(2):459-472
[26]Fourgeaud L, Traves P G, Tufail Y, et al.TAM receptors regulate multiple features of microglial physiology[J].Nature, 2016, 532(7598):240-244
[27]Schafer D P, Lehrman E K, Stevens B.The "quad-partite" synapse: microglia-synapse interactions in the developing and mature CNS[J].Glia, 2013, 61(1):24-36
[28]Derecki N C, Katzmarski N, Kipnis J, et al.Microglia as a critical player in both developmental and late-life CNS pathologies[J].Acta Neuropathologica, 2014, 128(3):333-345
[29]Wu Y W, Dissing-Olesen L, MacVicar B A, et al.Microglia: Dynamic Mediators of Synapse Development and Plasticity[J].Trends in Immunology, 2015, 36(10):605-613
[30]Hanisch U K.Microglia as a source and target of cytokines[J].Glia, 2002, 40(2):140-155
[31]Cameron B, Landreth G E.Inflammation,microglia,and Alzheimer's disease[J].Neurobiol Dis, 2010, 37(3):503-509
[32]Liddelow S A, Guttenplan K A, Larke L E C, et al.Neurotoxic reactive astrocytes are induced by activated microglia[J].Nature, 2017, 541(7638):481-487
[33]Deierborg T, Roybon L, Inacio A R, et al.Brain injury activates microglia that induce neural stem cell proliferation ex vivo and promote differentiation of neurosphere-derived cells into neurons and oligodendrocytes[J].Neuroscience, 2010, 171(4):1386-1396
[34]Perry V H, Holmes C.Microglial priming in neurodegenerative disease[J].Nat Rev Neurol, 2014, 10(4):217-224
[35]Blennow K, de Leon M J, Zetterberg H.Alzheimer's disease[J].Lancet, 2006, 368(9533):387-403
[36]Fonseca M I, Chu S H, Hernandez M X, et al.Cell-specific deletion of C1qa identifies microglia as the dominant source of C1q in mouse brain[J].J Neuroinflammation, 2017, 14(1):48-62
[37]Selkoe D J, Hardy J.The amyloid hypothesis of Alzheimer's disease at 25years[J].Embo Molecular Medicine, 2016, 8(6):595-608
[38]Abbott A, Dolgin E.Failed Alzheimer's trial does not kill leading theory of disease[J].Nature, 2016, 540(7631):15-16
[39]Polanco J C, Li C, Bodea L G, et al.Amyloid-beta and tau complexity - towards improved biomarkers and targeted therapies[J].Nat Rev Neurol, 2018, 14(1):22-39
[40]Forloni G, Artuso V, La Vitola P, et al.Oligomeropathies and pathogenesis of Alzheimer and Parkinson's diseases[J].Mov Disord, 2016, 31(6):771-781
[41]Hong S, Beja-Glasser V F, Nfonoyim B M, et al.Complement and microglia mediate early synapse loss in Alzheimer mouse models[J].Science, 2016, 352(6286):712-716
[42]Koenigsknecht-Talboo J, Landreth G E.Microglial phagocytosis induced by fibrillar beta-amyloid and IgGs are differentially regulated by proinflammatory cytokines[J].J Neurosci, 2005, 25(36):8240-8249
[43]von Bernhardi R, Ramirez G, Toro R, et al.Pro-inflammatory conditions promote neuronal damage mediated by Amyloid Precursor Protein and decrease its phagocytosis and degradation by microglial cells in culture[J].Neurobiol Dis, 2007, 26(1):153-164
[44]Weiner H L, Frenkel D.Immunology and immunotherapy of Alzheimer's disease[J].Nat Rev Immunol, 2006, 6(5):404-416
[45]Yeh F L, Hansen D V, Sheng M.TREM2,Microglia,and Neurodegenerative Diseases[J].Trends Mol Med, 2017, 23(6):512-533
[46]Terwel D, Steffensen K R, Verghese P B, et al.Critical role of astroglial apolipoprotein E and liver X receptor-alpha for microglial Abeta phagocytosis[J].J Neurosci, 2011, 31(19):7049-7059
[47]Jaworski T, Lechat B, Demedts D, et al.Dendritic degeneration,neurovascular defects,and inflammation precede neuronal loss in a mouse model for tau-mediated neurodegeneration[J].Am J Pathol, 2011, 179(4):2001-2015
[48]Britschgi M, Takeda-Uchimura Y, Rockenstein E, et al.Deficiency of terminal complement pathway inhibitor promotes neuronal tau pathology and degeneration in mice [J].J Neuroinflammation, 2012, 9(9):220-225
[49]Fonseca M I, Ager R R, Chu S H, et al.Treatment with a C5aR antagonist decreases pathology and enhances behavioral performance in murine models of Alzheimer's disease[J].J Immunol, 2009, 183(2):1375-83
[50]Asai H, Ikezu S, Tsunoda S, et al.Depletion of microglia and inhibition of exosome synthesis halt tau propagation[J].Nat Neurosci, 2015, 18(11):1584-1593
[51]Maphis N, Xu G, Kokiko-Cochran O N, et al.Reactive microglia drive tau pathology and contribute to the spreading of pathological tau in the brain[J].Brain, 2015, 138(Pt 6):1738-1755
[52]Cho S H, Sun B, Zhou Y, et al.CX3CR1 protein signaling modulates microglial activation and protects against plaque-independent cognitive deficits in a mouse model of Alzheimer disease[J].J Biol Chem, 2011, 286(37):32713-32722
[53]Bhaskar K, Konerth M, Kokiko-Cochran O N, et al.Regulation of tau pathology by the microglial fractalkine receptor[J].Neuron, 2010, 68(1):19-31
[54]Shi Y, Yamada K, Liddelow S A, et al.ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy[J].Nature, 2017, 549(7673):523-527
[55]Harris K P, Littleton J T.Transmission,Development,and Plasticity of Synapses[J].Genetics, 2015, 201(2):345-375
[56]Lin Y C, Koleske A J.Mechanisms of Synapse and Dendrite Maintenance and Their Disruption in Psychiatric and Neurodegenerative Disorders[J].Annual Review of Neuroscience, 2010, 33 (33):349-378
[57]Campagne M V, Wiesmann C, Brown E J.Macrophage complement receptors and pathogen clearance[J].Cellular Microbiology, 2007, 9(9):2095-2102
[58]Stephan A H, Barres B A, Stevens B.The Complement System: An Unexpected Role in Synaptic Pruning During Development and Disease[J].Annual Review of Neuroscience, 2012, 35(35):369-389
[59]Presumey J, Bialas A R, Carroll M C.Complement System in Neural Synapse Elimination in Development and Disease[J].Advances in Immunology, 2017, 135(135):53-79
[60]Courchesne E, Mouton P R, Calhoun M E, et al.Neuron Number and Size in Prefrontal Cortex of Children With Autism[J].Jama-Journal of the American Medical Association, 2011, 306(18):2001-2010
[61]Willison H J, Jacobs B C, van Doorn P A.Guillain-Barre syndrome[J].Lancet, 2016, 388(10045):717-727
[62]Zamanian J L, Xu L J, Foo L C, et al.Genomic Analysis of Reactive Astrogliosis[J].Journal of Neuroscience, 2012, 32(18):6391-6410
[63]Spangenberg E E, Lee R J, Najafi A R, et al.Eliminating microglia in Alzheimer' s mice prevents neuronal loss without modulating amyloid-beta pathology[J].Brain, 2016, 139(139):1265-1281
[64]Olmos-Alonso A, Schetters S T, Sri S, et al.Pharmacological targeting of CSF1R inhibits microglial proliferation and prevents the progression of Alzheimer's-like pathology[J].Brain, 2016, 139(Pt 3):891-907
[65]Paolicelli R C, Jawaid A, Henstridge C M, et al.TDP-43 Depletion in Microglia Promotes Amyloid Clearance but Also Induces Synapse Loss[J].Neuron, 2017, 95(2):297-308
[66]Rabinovich-Nikitin I, Ezra A, Barbiro B, et al.Chronic administration of AMD3100 increases survival and alleviates pathology in SOD1(G93A) mice model of ALS[J].J Neuroinflammation, 2016, 13(1):123-133
[67]Carty M, Bowie A G.Evaluating the role of Toll-like receptors in diseases of the central nervous system[J].Biochem Pharmacol, 2011, 81(7):825-837