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Current Alzheimer Research

Editor-in-Chief

ISSN (Print): 1567-2050
ISSN (Online): 1875-5828

Review Article

Microglia in Alzheimer’s Disease

Author(s): Patrick Süß and Johannes C.M. Schlachetzki*

Volume 17, Issue 1, 2020

Page: [29 - 43] Pages: 15

DOI: 10.2174/1567205017666200212155234

Price: $65

Abstract

Alzheimer’s Disease (AD) is the most frequent neurodegenerative disorder. Although proteinaceous aggregates of extracellular Amyloid-β (Aβ) and intracellular hyperphosphorylated microtubule- associated tau have long been identified as characteristic neuropathological hallmarks of AD, a disease- modifying therapy against these targets has not been successful. An emerging concept is that microglia, the innate immune cells of the brain, are major players in AD pathogenesis. Microglia are longlived tissue-resident professional phagocytes that survey and rapidly respond to changes in their microenvironment. Subpopulations of microglia cluster around Aβ plaques and adopt a transcriptomic signature specifically linked to neurodegeneration. A plethora of molecules and pathways associated with microglia function and dysfunction has been identified as important players in mediating neurodegeneration. However, whether microglia exert either beneficial or detrimental effects in AD pathology may depend on the disease stage.

In this review, we summarize the current knowledge about the stage-dependent role of microglia in AD, including recent insights from genetic and gene expression profiling studies as well as novel imaging techniques focusing on microglia in human AD pathology and AD mouse models.

Keywords: Microglia, Alzheimer's disease, genetics, transcriptomics, neurofibrillary tangles, Aβ plaques.

[1]
Shah H, Albanese E, Duggan C, Rudan I, Langa KM, Carrillo MC, et al. Research priorities to reduce the global burden of dementia by 2025. Lancet Neurol 15(12): 1285-94. (2016).
[http://dx.doi.org/10.1016/S1474-4422(16)30235-6] [PMID: 27751558]
[2]
Selkoe DJ, Hardy J. The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Mol Med 8(6): 595-608. (2016).
[http://dx.doi.org/10.15252/emmm.201606210] [PMID: 27025652]
[3]
Heneka MT, Golenbock DT, Latz E. Innate immunity in Alzheimer’s disease. Nat Immunol 16(3): 229-36. (2015).
[http://dx.doi.org/10.1038/ni.3102] [PMID: 25689443]
[4]
Ginhoux F, Greter M, Leboeuf M, Nandi S, See P, Gokhan S, et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330(6005): 841-5. (2010).
[http://dx.doi.org/10.1126/science.1194637] [PMID: 20966214]
[5]
Tay TL, Mai D, Dautzenberg J, Fernández-Klett F, Lin G, Datta M, et al. A new fate mapping system reveals context-dependent random or clonal expansion of microglia. Nat Neurosci 20(6): 793-803. (2017).
[http://dx.doi.org/10.1038/nn.4547] [PMID: 28414331]
[6]
Ajami B, Bennett JL, Krieger C, Tetzlaff W, Rossi FM. Local self-renewal can sustain CNS microglia maintenance and function throughout adult life. Nat Neurosci 10(12): 1538-43. (2007).
[http://dx.doi.org/10.1038/nn2014] [PMID: 18026097]
[7]
Askew K, Li K, Olmos-Alonso A, Garcia-Moreno F, Liang Y, Richardson P, et al. Coupled proliferation and apoptosis maintain the rapid turnover of microglia in the adult brain. Cell Rep 18(2): 391-405. (2017).
[http://dx.doi.org/10.1016/j.celrep.2016.12.041] [PMID: 28076784]
[8]
Réu P, Khosravi A, Bernard S, Mold J, Salehpour M, Alkass K, et al. The lifespan and turnover of microglia in the human brain. Cell Rep 20(4): 779-84. (2017).
[http://dx.doi.org/10.1016/j.celrep.2017.07.004] [PMID: 28746864]
[9]
Füger P, Hefendehl JK, Veeraraghavalu K, Wendeln AC, Schlosser C, Obermüller U, et al. Microglia turnover with aging and in an Alzheimer’s model via long-term in vivo single-cell imaging. Nat Neurosci 20(10): 1371-6. (2017).
[http://dx.doi.org/10.1038/nn.4631] [PMID: 28846081]
[10]
Nimmerjahn A, Kirchhoff F, Helmchen F. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308(5726): 1314-8. (2005).
[http://dx.doi.org/10.1126/science.1110647] [PMID: 15831717]
[11]
Davalos D, Grutzendler J, Yang G, Kim JV, Zuo Y, Jung S, et al. ATP mediates rapid microglial response to local brain injury in vivo. Nat Neurosci 8(6): 752-8. (2005).
[http://dx.doi.org/10.1038/nn1472] [PMID: 15895084]
[12]
Schlachetzki JC, Hüll M. Microglial activation in Alzheimer’s disease. Curr Alzheimer Res 6(6): 554-63. (2009).
[http://dx.doi.org/10.2174/156720509790147179] [PMID: 19747160]
[13]
Song WM, Colonna M. The identity and function of microglia in neurodegeneration. Nat Immunol 19(10): 1048-58. (2018).
[http://dx.doi.org/10.1038/s41590-018-0212-1] [PMID: 30250185]
[14]
Butovsky O, Weiner HL. Microglial signatures and their role in health and disease. Nat Rev Neurosci 19(10): 622-35. (2018).
[http://dx.doi.org/10.1038/s41583-018-0057-5] [PMID: 30206328]
[15]
Gosselin D, Skola D, Coufal NG, Holtman IR, Schlachetzki JCM, Sajti E, et al. An environment-dependent transcriptional network specifies human microglia identity. Science 356(6344) eaal3222 (2017).
[http://dx.doi.org/10.1126/science.aal3222] [PMID: 28546318]
[16]
Galatro TF, Holtman IR, Lerario AM, Vainchtein ID, Brouwer N, Sola PR, et al. Transcriptomic analysis of purified human cortical microglia reveals age-associated changes. Nat Neurosci 20(8): 1162-71. (2017).
[http://dx.doi.org/10.1038/nn.4597] [PMID: 28671693]
[17]
Nott A, Holtman IR, Coufal NG, Schlachetzki JCM, Yu M, Hu R, et al. Brain cell type-specific enhancer-promoter interactome maps and disease-risk association. Science 366(6469): 1134-9. (2019).
[http://dx.doi.org/10.1126/science.aay0793] [PMID: 31727856]
[18]
Masuda T, Sankowski R, Staszewski O, Böttcher C, Amann L, Scheiwe C, et al. Spatial and temporal heterogeneity of mouse and human microglia at single-cell resolution. Nature 566(7744): 388-92. (2019).
[http://dx.doi.org/10.1038/s41586-019-0924-x] [PMID: 30760929]
[19]
Böttcher C, Schlickeiser S, Sneeboer MAM, Kunkel D, Knop A, Paza E, et al. NBB-Psy. Human microglia regional heterogeneity and phenotypes determined by multiplexed single-cell mass cytometry. Nat Neurosci 22(1): 78-90. (2019).
[http://dx.doi.org/10.1038/s41593-018-0290-2] [PMID: 30559476]
[20]
Sims R, van der Lee SJ, Naj AC, Bellenguez C, Badarinarayan N, Jakobsdottir J, et al. ARUK Consortium. GERAD/PERADES, CHARGE, ADGC, EADI. Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer’s disease. Nat Genet 49(9): 1373-84. (2017).
[http://dx.doi.org/10.1038/ng.3916] [PMID: 28714976]
[21]
Jansen IE, Savage JE, Watanabe K, Bryois J, Williams DM, Steinberg S, et al. Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer’s disease risk. Nat Genet 51(3): 404-13. (2019).
[http://dx.doi.org/10.1038/s41588-018-0311-9] [PMID: 30617256]
[22]
Sala Frigerio C, Wolfs L, Fattorelli N, Thrupp N, Voytyuk I, Schmidt I, et al. The major risk factors for Alzheimer’s Disease: age, sex, and genes modulate the microglia response to Aβ plaques. Cell Rep 27(4): 1293-1306.e6. (2019).
[http://dx.doi.org/10.1016/j.celrep.2019.03.099] [PMID: 31018141]
[23]
Shi Y, Holtzman DM. Interplay between innate immunity and Alzheimer disease: APOE and TREM2 in the spotlight. Nat Rev Immunol 18(12): 759-72. (2018).
[http://dx.doi.org/10.1038/s41577-018-0051-1] [PMID: 30140051]
[24]
Namba Y, Tomonaga M, Kawasaki H, Otomo E, Ikeda K. Apolipoprotein E immunoreactivity in cerebral amyloid deposits and neurofibrillary tangles in Alzheimer’s disease and kuru plaque amyloid in Creutzfeldt-Jakob disease. Brain Res 541(1): 163-6. (1991).
[http://dx.doi.org/10.1016/0006-8993(91)91092-F] [PMID: 2029618]
[25]
Zhang Y, Chen K, Sloan SA, Bennett M, Scholze AR, O’Keeffe S, et al. An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex. J Neurosci 34(36): 11929-47. (2014).
[http://dx.doi.org/10.1523/JNEUROSCI.1860-14.2014] [PMID: 25186741]
[26]
Xu Q, Bernardo A, Walker D, Kanegawa T, Mahley RW, Huang Y. Profile and regulation of apolipoprotein E (ApoE) expression in the CNS in mice with targeting of green fluorescent protein gene to the ApoE locus. J Neurosci 26(19): 4985-94. (2006).
[http://dx.doi.org/10.1523/JNEUROSCI.5476-05.2006] [PMID: 16687490]
[27]
Kim J, Jiang H, Park S, Eltorai AEM, Stewart FR, Yoon H, et al. Haploinsufficiency of human APOE reduces amyloid deposition in a mouse model of amyloid-β amyloidosis. J Neurosci 31(49): 18007-12. (2011).
[http://dx.doi.org/10.1523/JNEUROSCI.3773-11.2011] [PMID: 22159114]
[28]
Shi Y, Yamada K, Liddelow SA, Smith ST, Zhao L, Luo W, et al. Alzheimer’s Disease Neuroimaging Initiative. ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy. Nature 549(7673): 523-7. (2017).
[http://dx.doi.org/10.1038/nature24016] [PMID: 28959956]
[29]
Liu CC, Zhao N, Fu Y, Wang N, Linares C, Tsai CW, et al. ApoE4 Accelerates Early Seeding of Amyloid Pathology. Neuron 96(5): 1024-1032.e3. (2017).
[http://dx.doi.org/10.1016/j.neuron.2017.11.013] [PMID: 29216449]
[30]
Keren-Shaul H, Spinrad A, Weiner A, Matcovitch-Natan O, Dvir-Szternfeld R, Ulland TK, et al. A unique microglia type associated with restricting development of Alzheimer’s disease. Cell 169(7): 1276-1290.e17. (2017).
[http://dx.doi.org/10.1016/j.cell.2017.05.018] [PMID: 28602351]
[31]
Krasemann S, Madore C, Cialic R, Baufeld C, Calcagno N, Fatimy RE, et al. The TREM2-APOE pathway drives the transcriptional phenotype of dysfunctional microglia in neurodegenerative diseases. Immunity 47(3): 566-581.e9. (2017).
[http://dx.doi.org/10.1016/j.immuni.2017.08.008] [PMID: 28930663]
[32]
Kang SS, Ebbert MTW, Baker KE, Cook C, Wang X, Sens JP, et al. Microglial translational profiling reveals a convergent APOE pathway from aging, amyloid, and tau. J Exp Med 215(9): 2235-45. (2018).
[http://dx.doi.org/10.1084/jem.20180653] [PMID: 30082275]
[33]
Guerreiro R, Wojtas A, Bras J, Carrasquillo M, Rogaeva E, Majounie E, et al. Alzheimer genetic analysis group. TREM2 variants in Alzheimer’s disease. N Engl J Med 368(2): 117-27. (2013)1.
[http://dx.doi.org/10.1056/NEJMoa1211851] [PMID: 23150934]
[34]
Jonsson T, Stefansson H, Steinberg S, Jonsdottir I, Jonsson PV, Snaedal J, et al. Variant of TREM2 associated with the risk of Alzheimer’s disease. N Engl J Med 368(2): 107-16. (2013).
[http://dx.doi.org/10.1056/NEJMoa1211103] [PMID: 23150908]
[35]
Kober DL, Alexander-Brett JM, Karch CM, Cruchaga C, Colonna M, Holtzman MJ, et al. Neurodegenerative disease mutations in TREM2 reveal a functional surface and distinct loss-of-function mechanisms. eLife 5. (2016).
[36]
Atagi Y, Liu CC, Painter MM, Chen XF, Verbeeck C, Zheng H, et al. Apolipoprotein E is a ligand for triggering receptor expressed on myeloid cells 2 (TREM2). J Biol Chem 290(43): 26043-50. (2015).
[http://dx.doi.org/10.1074/jbc.M115.679043] [PMID: 26374899]
[37]
Yeh FL, Wang Y, Tom I, Gonzalez LC, Sheng M. TREM2 Binds to apolipoproteins, including APOE and CLU/APOJ, and thereby facilitates uptake of amyloid-beta by microglia. Neuron 91(2): 328-40. (2016).
[http://dx.doi.org/10.1016/j.neuron.2016.06.015] [PMID: 27477018]
[38]
Zhao Y, Wu X, Li X, Jiang LL, Gui X, Liu Y, et al. TREM2 is a receptor for β-amyloid that mediates microglial function. Neuron 97(5): 1023-1031.e7. (2018).
[http://dx.doi.org/10.1016/j.neuron.2018.01.031] [PMID: 29518356]
[39]
Wang Y, Cella M, Mallinson K, Ulrich JD, Young KL, Robinette ML, et al. TREM2 lipid sensing sustains the microglial response in an Alzheimer’s disease model. Cell 160(6): 1061-71. (2015).
[http://dx.doi.org/10.1016/j.cell.2015.01.049] [PMID: 25728668]
[40]
Hammond TR, Marsh SE, Stevens B. Immune signaling in neurodegeneration. Immunity 50(4): 955-74. (2019).
[http://dx.doi.org/10.1016/j.immuni.2019.03.016] [PMID: 30995509]
[41]
Schlepckow K, Kleinberger G, Fukumori A, Feederle R, Lichtenthaler SF, Steiner H, et al. An Alzheimer-associated TREM2 variant occurs at the ADAM cleavage site and affects shedding and phagocytic function. EMBO Mol Med 9(10): 1356-65. (2017).
[http://dx.doi.org/10.15252/emmm.201707672] [PMID: 28855300]
[42]
Zhong L, Chen XF, Wang T, Wang Z, Liao C, Wang Z, et al. Soluble TREM2 induces inflammatory responses and enhances microglial survival. J Exp Med 214(3): 597-607. (2017).
[http://dx.doi.org/10.1084/jem.20160844] [PMID: 28209725]
[43]
Piccio L, Deming Y, Del-Águila JL, Ghezzi L, Holtzman DM, Fagan AM, et al. Cerebrospinal fluid soluble TREM2 is higher in Alzheimer disease and associated with mutation status. Acta Neuropathol 131(6): 925-33. (2016).
[http://dx.doi.org/10.1007/s00401-016-1533-5] [PMID: 26754641]
[44]
Ewers M, Franzmeier N, Suárez-Calvet M, Morenas-Rodriguez E, Caballero MAA, Kleinberger G, et al. Alzheimer’s disease neuroimaging initiative. Increased soluble TREM2 in cerebrospinal fluid is associated with reduced cognitive and clinical decline in Alzheimer’s disease. Sci Transl Med 11(507): 6221. (2019).
[http://dx.doi.org/10.1126/scitranslmed.aav6221] [PMID: 31462511]
[45]
Suárez-Calvet M, Morenas-Rodríguez E, Kleinberger G, Schlepckow K, Caballero AMM, Franzmeier N, et al. Alzheimer’s Disease Neuroimaging Initiative. Early increase of CSF sTREM2 in Alzheimer’s disease is associated with tau related-neurodegeneration but not with amyloid-β pathology. Mol Neurodegener 14(1): 1. (2019).
[http://dx.doi.org/10.1186/s13024-018-0301-5] [PMID: 30630532]
[46]
Takahashi K, Rochford CD, Neumann H. Clearance of apoptotic neurons without inflammation by microglial triggering receptor expressed on myeloid cells-2. J Exp Med 201(4): 647-57. (2005).
[http://dx.doi.org/10.1084/jem.20041611] [PMID: 15728241]
[47]
Ulland TK, Colonna M. TREM2 - a key player in microglial biology and Alzheimer disease. Nat Rev Neurol 14(11): 667-75. (2018).
[http://dx.doi.org/10.1038/s41582-018-0072-1] [PMID: 30266932]
[48]
Ulland TK, Song WM, Huang SC, Ulrich JD, Sergushichev A, Beatty WL, et al. TREM2 maintains microglial metabolic fitness in Alzheimer’s disease. Cell 170(4): 649-663.e13. (2017).
[http://dx.doi.org/10.1016/j.cell.2017.07.023] [PMID: 28802038]
[49]
Jay TR, Hirsch AM, Broihier ML, Miller CM, Neilson LE, Ransohoff RM, et al. Disease progression-dependent effects of TREM2 deficiency in a mouse model of Alzheimer’s Disease. J Neurosci 37(3): 637-47. (2017).
[http://dx.doi.org/10.1523/JNEUROSCI.2110-16.2016] [PMID: 28100745]
[50]
Wang Y, Ulland TK, Ulrich JD, Song W, Tzaferis JA, Hole JT, et al. TREM2-mediated early microglial response limits diffusion and toxicity of amyloid plaques. J Exp Med 213(5): 667-75. (2016).
[http://dx.doi.org/10.1084/jem.20151948] [PMID: 27091843]
[51]
Leyns CEG, Ulrich JD, Finn MB, Stewart FR, Koscal LJ, Remolina Serrano J, et al. TREM2 deficiency attenuates neuroinflammation and protects against neurodegeneration in a mouse model of tauopathy. Proc Natl Acad Sci USA 114(43): 11524-9. (2017).
[http://dx.doi.org/10.1073/pnas.1710311114] [PMID: 29073081]
[52]
Sayed FA, Telpoukhovskaia M, Kodama L, Li Y, Zhou Y, Le D, et al. Differential effects of partial and complete loss of TREM2 on microglial injury response and tauopathy. Proc Natl Acad Sci USA 2018; 115(40): 10172-7.
[http://dx.doi.org/10.1073/pnas.1811411115] [PMID: 30232263]
[53]
Parhizkar S, Arzberger T, Brendel M, Kleinberger G, Deussing M, Focke C, et al. Loss of TREM2 function increases amyloid seeding but reduces plaque-associated ApoE. Nat Neurosci 22(2): 191-204. (2019).
[http://dx.doi.org/10.1038/s41593-018-0296-9] [PMID: 30617257]
[54]
Griciuc A, Serrano-Pozo A, Parrado AR, Lesinski AN, Asselin CN, Mullin K, et al. Alzheimer’s disease risk gene CD33 inhibits microglial uptake of amyloid beta. Neuron 78(4): 631-43. (2013).
[http://dx.doi.org/10.1016/j.neuron.2013.04.014] [PMID: 23623698]
[55]
Estus S, Shaw BC, Devanney N, Katsumata Y, Press EE, Fardo DW. Evaluation of CD33 as a genetic risk factor for Alzheimer’s disease. Acta Neuropathol 138(2): 187-99. (2019).
[http://dx.doi.org/10.1007/s00401-019-02000-4] [PMID: 30949760]
[56]
Griciuc A, Patel S, Federico AN, Choi SH, Innes BJ, Oram MK, et al. TREM2 Acts downstream of cd33 in modulating microglial pathology in Alzheimer's disease. Neuron 103(5): 820-35. e7 (2019).
[http://dx.doi.org/10.1016/j.neuron.2019.06.010]
[57]
Hollingworth P, Harold D, Sims R, Gerrish A, Lambert JC, Carrasquillo MM, et al. Alzheimer’s disease neuroimaging initiative; CHARGE consortium; EADI1 consortium. Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer’s disease. Nat Genet 43(5): 429-35. (2011).
[http://dx.doi.org/10.1038/ng.803] [PMID: 21460840]
[58]
Sakae N, Liu CC, Shinohara M, Frisch-Daiello J, Ma L, Yamazaki Y, et al. ABCA7 deficiency accelerates amyloid-β generation and Alzheimer’s neuronal pathology. J Neurosci 36(13): 3848-59. (2016).
[http://dx.doi.org/10.1523/JNEUROSCI.3757-15.2016] [PMID: 27030769]
[59]
Aikawa T, Ren Y, Yamazaki Y, Tachibana M, Johnson M, Anderson CT, et al. ABCA7 haplodeficiency disturbs microglial immune responses in the mouse brain. Proc Natl Acad Sci USA 116(47): 23790-6. (2019).
[http://dx.doi.org/10.1073/pnas.1908529116] [PMID: 31690660]
[60]
Magno L, Lessard CB, Martins M, Lang V, Cruz P, Asi Y, et al. Alzheimer’s disease phospholipase C-gamma-2 (PLCG2) protective variant is a functional hypermorph. Alzheimers Res Ther 11(1): 16. (2019).
[http://dx.doi.org/10.1186/s13195-019-0469-0] [PMID: 30711010]
[61]
Satoh JI, Kino Y, Yanaizu M, Tosaki Y, Sakai K, Ishida T, et al. Microglia express ABI3 in the brains of Alzheimer’s disease and Nasu-Hakola disease. Intractable Rare Dis Res 6(4): 262-8. (2017).
[http://dx.doi.org/10.5582/irdr.2017.01073] [PMID: 29259854]
[62]
Huang KL, Marcora E, Pimenova AA, Di Narzo AF, Kapoor M, Jin SC, et al. International Genomics of Alzheimer’s Project; Alzheimer’s Disease Neuroimaging Initiative. A common haplotype lowers PU.1 expression in myeloid cells and delays onset of Alzheimer’s disease. Nat Neurosci 20(8): 1052-61. (2017).
[http://dx.doi.org/10.1038/nn.4587] [PMID: 28628103]
[63]
Gjoneska E, Pfenning AR, Mathys H, Quon G, Kundaje A, Tsai LH, et al. Conserved epigenomic signals in mice and humans reveal immune basis of Alzheimer’s disease. Nature 518(7539): 365-9. (2015).
[http://dx.doi.org/10.1038/nature14252] [PMID: 25693568]
[64]
Wendeln AC, Degenhardt K, Kaurani L, Gertig M, Ulas T, Jain G, et al. Innate immune memory in the brain shapes neurological disease hallmarks. Nature 556(7701): 332-8. (2018).
[http://dx.doi.org/10.1038/s41586-018-0023-4] [PMID: 29643512]
[65]
Datta M, Staszewski O, Raschi E, Frosch M, Hagemeyer N, Tay TL, et al. Histone deacetylases 1 and 2 regulate microglia function during development, homeostasis, and neurodegeneration in a context-dependent manner. Immunity 48(3): 514-529.e6. (2018).
[http://dx.doi.org/10.1016/j.immuni.2018.02.016] [PMID: 29548672]
[66]
Wirths O, Breyhan H, Marcello A, Cotel MC, Brück W, Bayer TA. Inflammatory changes are tightly associated with neurodegeneration in the brain and spinal cord of the APP/PS1KI mouse model of Alzheimer’s disease. Neurobiol Aging 31(5): 747-57. (2010).
[http://dx.doi.org/10.1016/j.neurobiolaging.2008.06.011] [PMID: 18657882]
[67]
Heneka MT, Sastre M, Dumitrescu-Ozimek L, Dewachter I, Walter J, Klockgether T, et al. Focal glial activation coincides with increased BACE1 activation and precedes amyloid plaque deposition in APP[V717I] transgenic mice. J Neuroinflammation 2: 22. (2005).
[http://dx.doi.org/10.1186/1742-2094-2-22] [PMID: 16212664]
[68]
Yoshiyama Y, Higuchi M, Zhang B, Huang SM, Iwata N, Saido TC, et al. Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron 53(3): 337-51. (2007).
[http://dx.doi.org/10.1016/j.neuron.2007.01.010] [PMID: 17270732]
[69]
Meyer-Luehmann M, Spires-Jones TL, Prada C, Garcia-Alloza M, de Calignon A, Rozkalne A, et al. Rapid appearance and local toxicity of amyloid-beta plaques in a mouse model of Alzheimer’s disease. Nature 451(7179): 720-4. (2008).
[http://dx.doi.org/10.1038/nature06616] [PMID: 18256671]
[70]
Bolmont T, Haiss F, Eicke D, Radde R, Mathis CA, Klunk WE, et al. Dynamics of the microglial/amyloid interaction indicate a role in plaque maintenance. J Neurosci 28(16): 4283-92. (2008).
[http://dx.doi.org/10.1523/JNEUROSCI.4814-07.2008] [PMID: 18417708]
[71]
Yuan P, Condello C, Keene CD, Wang Y, Bird TD, Paul SM, et al. TREM2 haplodeficiency in mice and humans impairs the microglia barrier function leading to decreased amyloid compaction and severe axonal dystrophy. Neuron 92(1): 252-64. (2016).
[http://dx.doi.org/10.1016/j.neuron.2016.09.016] [PMID: 27710785]
[72]
Ulrich JD, Ulland TK, Mahan TE, Nyström S, Nilsson KP, Song WM, et al. ApoE facilitates the microglial response to amyloid plaque pathology. J Exp Med 215(4): 1047-58. (2018).
[http://dx.doi.org/10.1084/jem.20171265] [PMID: 29483128]
[73]
Orre M, Kamphuis W, Osborn LM, Jansen AHP, Kooijman L, Bossers K, et al. Isolation of glia from Alzheimer’s mice reveals inflammation and dysfunction. Neurobiol Aging 35(12): 2746-60. (2014).
[http://dx.doi.org/10.1016/j.neurobiolaging.2014.06.004] [PMID: 25002035]
[74]
Kamphuis W, Kooijman L, Schetters S, Orre M, Hol EM. Transcriptional profiling of CD11c-positive microglia accumulating around amyloid plaques in a mouse model for Alzheimer’s disease. Biochim Biophys Acta 1862(10): 1847-60. (2016).
[http://dx.doi.org/10.1016/j.bbadis.2016.07.007] [PMID: 27425031]
[75]
Yin Z, Raj D, Saiepour N, Van Dam D, Brouwer N, Holtman IR, et al. Immune hyperreactivity of Aβ plaque-associated microglia in Alzheimer’s disease. Neurobiol Aging 55: 115-22. (2017).
[http://dx.doi.org/10.1016/j.neurobiolaging.2017.03.021] [PMID: 28434692]
[76]
Mathys H, Adaikkan C, Gao F, Young JZ, Manet E, Hemberg M, et al. Temporal tracking of microglia activation in neurodegeneration at single-cell resolution. Cell Rep 21(2): 366-80. (2017).
[http://dx.doi.org/10.1016/j.celrep.2017.09.039] [PMID: 29020624]
[77]
Butovsky O, Jedrychowski MP, Moore CS, Cialic R, Lanser AJ, Gabriely G, et al. Identification of a unique TGF-β-dependent molecular and functional signature in microglia. Nat Neurosci 17(1): 131-43. (2014).
[http://dx.doi.org/10.1038/nn.3599] [PMID: 24316888]
[78]
Hickman SE, Kingery ND, Ohsumi TK, Borowsky ML, Wang LC, Means TK, et al. The microglial sensome revealed by direct RNA sequencing. Nat Neurosci 16(12): 1896-905. (2013).
[http://dx.doi.org/10.1038/nn.3554] [PMID: 24162652]
[79]
Holtman IR, Raj DD, Miller JA, Schaafsma W, Yin Z, Brouwer N, et al. Induction of a common microglia gene expression signature by aging and neurodegenerative conditions: a co-expression meta-analysis. Acta Neuropathol Commun 3: 31. (2015).
[http://dx.doi.org/10.1186/s40478-015-0203-5] [PMID: 26001565]
[80]
Mrdjen D, Pavlovic A, Hartmann FJ, Schreiner B, Utz SG, Leung BP, et al. High-dimensional single-cell mapping of central nervous system immune cells reveals distinct myeloid subsets in health, aging, and disease. Immunity 48(3): 599. (2018).
[http://dx.doi.org/10.1016/j.immuni.2018.02.014] [PMID: 29562204]
[81]
Bisht K, Sharma KP, Lecours C, Sánchez MG, El Hajj H, Milior G, et al. Dark microglia: a new phenotype predominantly associated with pathological states. Glia 64(5): 826-39. (2016).
[http://dx.doi.org/10.1002/glia.22966] [PMID: 26847266]
[82]
El Hajj H, Savage JC, Bisht K, Parent M, Vallières L, Rivest S, et al. Ultrastructural evidence of microglial heterogeneity in Alzheimer’s disease amyloid pathology. J Neuroinflammation 16(1): 87. (2019).
[http://dx.doi.org/10.1186/s12974-019-1473-9] [PMID: 30992040]
[83]
Itagaki S, McGeer PL, Akiyama H, Zhu S, Selkoe D. Relationship of microglia and astrocytes to amyloid deposits of Alzheimer disease. J Neuroimmunol 24(3): 173-82. (1989).
[http://dx.doi.org/10.1016/0165-5728(89)90115-X] [PMID: 2808689]
[84]
Mildner A, Huang H, Radke J, Stenzel W, Priller J. P2Y12 receptor is expressed on human microglia under physiological conditions throughout development and is sensitive to neuroinflammatory diseases. Glia 65(2): 375-87. (2017).
[http://dx.doi.org/10.1002/glia.23097] [PMID: 27862351]
[85]
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 79(1-2): 195-200. (1987).
[http://dx.doi.org/10.1016/0304-3940(87)90696-3] [PMID: 3670729]
[86]
Boza-Serrano A, Ruiz R, Sanchez-Varo R, García-Revilla J, Yang Y, Jimenez-Ferrer I, et al. Galectin-3, a novel endogenous TREM2 ligand, detrimentally regulates inflammatory response in Alzheimer’s disease. Acta Neuropathol 138(2): 251-73. (2019).
[http://dx.doi.org/10.1007/s00401-019-02013-z] [PMID: 31006066]
[87]
Streit WJ, Braak H, Xue QS, Bechmann I. Dystrophic (senescent) rather than activated microglial cells are associated with tau pathology and likely precede neurodegeneration in Alzheimer’s disease. Acta Neuropathol 118(4): 475-85. (2009).
[http://dx.doi.org/10.1007/s00401-009-0556-6] [PMID: 19513731]
[88]
Tischer J, Krueger M, Mueller W, Staszewski O, Prinz M, Streit WJ, et al. Inhomogeneous distribution of Iba-1 characterizes microglial pathology in Alzheimer’s disease. Glia 64(9): 1562-72. (2016).
[http://dx.doi.org/10.1002/glia.23024] [PMID: 27404378]
[89]
Mathys H, Davila-Velderrain J, Peng Z, Gao F, Mohammadi S, Young JZ, et al. Single-cell transcriptomic analysis of Alzheimer’s disease. Nature 570(7761): 332-7. (2019).
[http://dx.doi.org/10.1038/s41586-019-1195-2] [PMID: 31042697]
[90]
Friedman BA, Srinivasan K, Ayalon G, Meilandt WJ, Lin H, Huntley MA, et al. Diverse brain myeloid expression profiles reveal distinct microglial activation states and aspects of Alzheimer’s disease not evident in mouse models. Cell Rep 22(3): 832-47. (2018).
[http://dx.doi.org/10.1016/j.celrep.2017.12.066] [PMID: 29346778]
[91]
Olah M, Patrick E, Villani AC, Xu J, White CC, Ryan K, et al. A transcriptomic atlas of aged human microglia. Nat Commun 9(1): 539. (2018).
[http://dx.doi.org/10.1038/s41467-018-02926-5] [PMID: 29416036]
[92]
Dani M, Wood M, Mizoguchi R, Fan Z, Walker Z, Morgan R, et al. Microglial activation correlates in vivo with both tau and amyloid in Alzheimer’s disease. Brain 141(9): 2740-54. (2018).
[http://dx.doi.org/10.1093/brain/awy188] [PMID: 30052812]
[93]
Fan Z, Brooks DJ, Okello A, Edison P. An early and late peak in microglial activation in Alzheimer’s disease trajectory. Brain 140(3): 792-803. (2017).
[http://dx.doi.org/10.1093/brain/aww349] [PMID: 28122877]
[94]
Hamelin L, Lagarde J, Dorothée G, Leroy C, Labit M, Comley RA, et al. Clinical IMABio3 team. Early and protective microglial activation in Alzheimer’s disease: a prospective study using 18F-DPA-714 PET imaging. Brain 139(Pt 4): 1252-64. (2016).
[http://dx.doi.org/10.1093/brain/aww017] [PMID: 26984188]
[95]
Zhang Y, Sloan SA, Clarke LE, Caneda C, Plaza CA, Blumenthal PD, et al. Purification and characterization of progenitor and mature human astrocytes reveals transcriptional and functional differences with mouse. Neuron 89(1): 37-53. (2016).
[http://dx.doi.org/10.1016/j.neuron.2015.11.013] [PMID: 26687838]
[96]
Bennett ML, Bennett FC, Liddelow SA, Ajami B, Zamanian JL, Fernhoff NB, et al. New tools for studying microglia in the mouse and human CNS. Proc Natl Acad Sci USA 113(12): E1738-46. (2016).
[http://dx.doi.org/10.1073/pnas.1525528113] [PMID: 26884166]
[97]
Villa A, Klein B, Janssen B, Pedragosa J, Pepe G, Zinnhardt B, et al. Identification of new molecular targets for PET imaging of the microglial anti-inflammatory activation state. Theranostics 8(19): 5400-18. (2018).
[http://dx.doi.org/10.7150/thno.25572] [PMID: 30555554]
[98]
Horti AG, Naik R, Foss CA, Minn I, Misheneva V, Du Y, et al. PET imaging of microglia by targeting macrophage colony-stimulating factor 1 receptor (CSF1R). Proc Natl Acad Sci USA 116(5): 1686-91. (2019).
[http://dx.doi.org/10.1073/pnas.1812155116] [PMID: 30635412]
[99]
Song M, Jin J, Lim JE, Kou J, Pattanayak A, Rehman JA, et al. TLR4 mutation reduces microglial activation, increases Aβ deposits and exacerbates cognitive deficits in a mouse model of Alzheimer’s disease. J Neuroinflammation 8: 92. (2011).
[http://dx.doi.org/10.1186/1742-2094-8-92] [PMID: 21827663]
[100]
Richard KL, Filali M, Préfontaine P, Rivest S. Toll-like receptor 2 acts as a natural innate immune receptor to clear amyloid beta 1-42 and delay the cognitive decline in a mouse model of Alzheimer’s disease. J Neurosci 28(22): 5784-93. (2008).
[http://dx.doi.org/10.1523/JNEUROSCI.1146-08.2008] [PMID: 18509040]
[101]
Sarlus H, Heneka MT. Microglia in Alzheimer’s disease. J Clin Invest 127(9): 3240-9. (2017).
[http://dx.doi.org/10.1172/JCI90606] [PMID: 28862638]
[102]
Liu Y, Walter S, Stagi M, Cherny D, Letiembre M, Schulz-Schaeffer W, et al. LPS receptor (CD14): a receptor for phagocytosis of Alzheimer’s amyloid peptide. Brain 128(Pt 8): 1778-89. (2005).
[http://dx.doi.org/10.1093/brain/awh531] [PMID: 15857927]
[103]
Reed-Geaghan EG, Reed QW, Cramer PE, Landreth GE. Deletion of CD14 attenuates Alzheimer’s disease pathology by influencing the brain’s inflammatory milieu. J Neurosci 30(46): 15369-73. (2010).
[http://dx.doi.org/10.1523/JNEUROSCI.2637-10.2010] [PMID: 21084593]
[104]
El Khoury JB, Moore KJ, Means TK, Leung J, Terada K, Toft M, et al. CD36 mediates the innate host response to beta-amyloid. J Exp Med 197(12): 1657-66. (2003).
[http://dx.doi.org/10.1084/jem.20021546] [PMID: 12796468]
[105]
Coraci IS, Husemann J, Berman JW, Hulette C, Dufour JH, Campanella GK, et al. 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. (2002).
[http://dx.doi.org/10.1016/S0002-9440(10)64354-4] [PMID: 11786404]
[106]
Origlia N, Bonadonna C, Rosellini A, Leznik E, Arancio O, Yan SS, et al. Microglial receptor for advanced glycation end product-dependent signal pathway drives beta-amyloid-induced synaptic depression and long-term depression impairment in entorhinal cortex. J Neurosci 30(34): 11414-25. (2010).
[http://dx.doi.org/10.1523/JNEUROSCI.2127-10.2010] [PMID: 20739563]
[107]
Vodopivec I, Galichet A, Knobloch M, Bierhaus A, Heizmann CW, Nitsch RM. RAGE does not affect amyloid pathology in transgenic ArcAbeta mice. Neurodegener Dis 6(5-6): 270-80. (2009).
[http://dx.doi.org/10.1159/000261723] [PMID: 20145420]
[108]
El Khoury J, Hickman SE, Thomas CA, Cao L, Silverstein SC, Loike JD. Scavenger receptor-mediated adhesion of microglia to beta-amyloid fibrils. Nature 382(6593): 716-9. (1996).
[http://dx.doi.org/10.1038/382716a0] [PMID: 8751442]
[109]
Frenkel D, Wilkinson K, Zhao L, Hickman SE, Means TK, Puckett L, et al. Scara1 deficiency impairs clearance of soluble amyloid-β by mononuclear phagocytes and accelerates Alzheimer’s-like disease progression. Nat Commun 4: 2030. (2013).
[http://dx.doi.org/10.1038/ncomms3030] [PMID: 23799536]
[110]
Jiang H, Burdick D, Glabe CG, Cotman CW, Tenner AJ. beta-Amyloid activates complement by binding to a specific region of the collagen-like domain of the C1q A chain. J Immunol 152(10): 5050-9. (1994).
[PMID: 8176223]
[111]
Afagh A, Cummings BJ, Cribbs DH, Cotman CW, Tenner AJ. Localization and cell association of C1q in Alzheimer’s disease brain. Exp Neurol 138(1): 22-32. (1996).
[http://dx.doi.org/10.1006/exnr.1996.0043] [PMID: 8593893]
[112]
Yin C, Ackermann S, Ma Z, Mohanta SK, Zhang C, Li Y, et al. ApoE attenuates unresolvable inflammation by complex formation with activated C1q. Nat Med 25(3): 496-506. (2019).
[http://dx.doi.org/10.1038/s41591-018-0336-8] [PMID: 30692699]
[113]
Frackowiak J, Wisniewski HM, Wegiel J, Merz GS, Iqbal K, Wang KC. Ultrastructure of the microglia that phagocytose amyloid and the microglia that produce beta-amyloid fibrils. Acta Neuropathol 84(3): 225-33. (1992).
[http://dx.doi.org/10.1007/BF00227813] [PMID: 1414275]
[114]
Halle A, Hornung V, Petzold GC, Stewart CR, Monks BG, Reinheckel T, et al. The NALP3 inflammasome is involved in the innate immune response to amyloid-beta. Nat Immunol 9(8): 857-65. (2008).
[http://dx.doi.org/10.1038/ni.1636] [PMID: 18604209]
[115]
Heneka MT, McManus RM, Latz E. Inflammasome signalling in brain function and neurodegenerative disease. Nat Rev Neurosci 19(10): 610-21. (2018).
[http://dx.doi.org/10.1038/s41583-018-0055-7] [PMID: 30206330]
[116]
Heneka MT, Kummer MP, Stutz A, Delekate A, Schwartz S, Vieira-Saecker A, et al. NLRP3 is activated in Alzheimer’s disease and contributes to pathology in APP/PS1 mice. Nature 493(7434): 674-8. (2013).
[http://dx.doi.org/10.1038/nature11729] [PMID: 23254930]
[117]
Rangaraju S, Gearing M, Jin LW, Levey A. Potassium channel Kv1.3 is highly expressed by microglia in human Alzheimer’s disease. J Alzheimers Dis 44(3): 797-808. (2015).
[http://dx.doi.org/10.3233/JAD-141704] [PMID: 25362031]
[118]
Madry C, Kyrargyri V, Arancibia-Cárcamo IL, Jolivet R, Kohsaka S, Bryan RM, et al. Microglial ramification, surveillance, and interleukin-1β release are regulated by the two-pore domain K+ channel THIK-1. Neuron 97(2): 299-312.e6. (2018).
[PMID: 29290552]
[119]
Venegas C, Kumar S, Franklin BS, Dierkes T, Brinkschulte R, Tejera D, et al. Microglia-derived ASC specks cross-seed amyloid-β in Alzheimer’s disease. Nature 552(7685): 355-61. (2017).
[http://dx.doi.org/10.1038/nature25158] [PMID: 29293211]
[120]
Sosna J, Philipp S, Albay R III, Reyes-Ruiz JM, Baglietto-Vargas D, LaFerla FM, et al. Early long-term administration of the CSF1R inhibitor PLX3397 ablates microglia and reduces accumulation of intraneuronal amyloid, neuritic plaque deposition and pre-fibrillar oligomers in 5XFAD mouse model of Alzheimer’s disease. Mol Neurodegener 13(1): 11. (2018).
[http://dx.doi.org/10.1186/s13024-018-0244-x] [PMID: 29490706]
[121]
Spangenberg E, Severson PL, Hohsfield LA, et al. Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model. Nat Commun 10(1): 3758. (2019).
[http://dx.doi.org/10.1038/s41467-019-11674-z] [PMID: 31434879]
[122]
Jay TR, Miller CM, Cheng PJ, Graham LC, Bemiller S, Broihier ML, et al. TREM2 deficiency eliminates TREM2+ inflammatory macrophages and ameliorates pathology in Alzheimer’s disease mouse models. J Exp Med 212(3): 287-95. (2015).
[http://dx.doi.org/10.1084/jem.20142322] [PMID: 25732305]
[123]
Hong S, Beja-Glasser VF, Nfonoyim BM, Frouin A, Li S, Ramakrishnan S, et al. Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science 352(6286): 712-6. (2016).
[http://dx.doi.org/10.1126/science.aad8373] [PMID: 27033548]
[124]
Qiu WQ, Walsh DM, Ye Z, Vekrellis K, Zhang J, Podlisny MB, et al. Insulin-degrading enzyme regulates extracellular levels of amyloid beta-protein by degradation. J Biol Chem 273(49): 32730-8. (1998).
[http://dx.doi.org/10.1074/jbc.273.49.32730] [PMID: 9830016]
[125]
Iwata N, Tsubuki S, Takaki Y, Shirotani K, Lu B, Gerard NP, et al. Metabolic regulation of brain Abeta by neprilysin. Science 292(5521): 1550-2. (2001).
[http://dx.doi.org/10.1126/science.1059946] [PMID: 11375493]
[126]
Hickman SE, Allison EK, El Khoury J. Microglial dysfunction and defective beta-amyloid clearance pathways in aging Alzheimer’s disease mice. J Neurosci 28(33): 8354-60. (2008).
[http://dx.doi.org/10.1523/JNEUROSCI.0616-08.2008] [PMID: 18701698]
[127]
Yan P, Hu X, Song H, Yin K, Bateman RJ, Cirrito JR, et al. Matrix metalloproteinase-9 degrades amyloid-beta fibrils in vitro and compact plaques in situ. J Biol Chem 281(34): 24566-74. (2006).
[http://dx.doi.org/10.1074/jbc.M602440200] [PMID: 16787929]
[128]
Krabbe G, Halle A, Matyash V, Rinnenthal JL, Eom GD, Bernhardt U, et al. Functional impairment of microglia coincides with Beta-amyloid deposition in mice with Alzheimer-like pathology. PLoS One 8(4) e60921 (2013).
[http://dx.doi.org/10.1371/journal.pone.0060921] [PMID: 23577177]
[129]
Streit WJ, Sammons NW, Kuhns AJ, Sparks DL. Dystrophic microglia in the aging human brain. Glia 45(2): 208-12. (2004).
[http://dx.doi.org/10.1002/glia.10319] [PMID: 14730714]
[130]
Pluvinage JV, Haney MS, Smith BAH, Sun J, Iram T, Bonanno L, et al. CD22 blockade restores homeostatic microglial phagocytosis in ageing brains. Nature 568(7751): 187-92. (2019).
[http://dx.doi.org/10.1038/s41586-019-1088-4] [PMID: 30944478]
[131]
Simard AR, Soulet D, Gowing G, Julien JP, Rivest S. Bone marrow-derived microglia play a critical role in restricting senile plaque formation in Alzheimer’s disease. Neuron 49(4): 489-502. (2006).
[http://dx.doi.org/10.1016/j.neuron.2006.01.022] [PMID: 16476660]
[132]
Town T, Laouar Y, Pittenger C, Mori T, Szekely CA, Tan J, et al. Blocking TGF-beta-Smad2/3 innate immune signaling mitigates Alzheimer-like pathology. Nat Med 14(6): 681-7. (2008).
[http://dx.doi.org/10.1038/nm1781] [PMID: 18516051]
[133]
Prinz M, Priller J. The role of peripheral immune cells in the CNS in steady state and disease. Nat Neurosci 20(2): 136-44. (2017).
[http://dx.doi.org/10.1038/nn.4475] [PMID: 28092660]
[134]
Mildner A, Schlevogt B, Kierdorf K, Böttcher C, Erny D, Kummer MP, et al. Distinct and non-redundant roles of microglia and myeloid subsets in mouse models of Alzheimer’s disease. J Neurosci 31(31): 11159-71. (2011).
[http://dx.doi.org/10.1523/JNEUROSCI.6209-10.2011] [PMID: 21813677]
[135]
Bien-Ly N, Boswell CA, Jeet S, Beach TG, Hoyte K, Luk W, et al. Lack of widespread BBB disruption in Alzheimer’s disease models: focus on therapeutic antibodies. Neuron 88(2): 289-97. (2015).
[http://dx.doi.org/10.1016/j.neuron.2015.09.036] [PMID: 26494278]
[136]
Frenkel D, Puckett L, Petrovic S, Xia W, Chen G, Vega J, et al. A nasal proteosome adjuvant activates microglia and prevents amyloid deposition. Ann Neurol 63(5): 591-601. (2008).
[http://dx.doi.org/10.1002/ana.21340] [PMID: 18360829]
[137]
Bolós M, Llorens-Martín M, Jurado-Arjona J, Hernández F, Rábano A, Avila J. Direct evidence of internalization of tau by microglia in vitro and in vivo. J Alzheimers Dis 50(1): 77-87. (2016).
[http://dx.doi.org/10.3233/JAD-150704] [PMID: 26638867]
[138]
Brelstaff J, Tolkovsky AM, Ghetti B, Goedert M, Spillantini MG. Living neurons with tau filaments aberrantly expose phosphatidylserine and are phagocytosed by microglia. Cell Rep 24(8): 1939-1948.e4. (2018).
[http://dx.doi.org/10.1016/j.celrep.2018.07.072] [PMID: 30134156]
[139]
Asai H, Ikezu S, Tsunoda S, Medalla M, Luebke J, Haydar T, et al. Depletion of microglia and inhibition of exosome synthesis halt tau propagation. Nat Neurosci 18(11): 1584-93. (2015).
[http://dx.doi.org/10.1038/nn.4132] [PMID: 26436904]
[140]
Bhaskar K, Konerth M, Kokiko-Cochran ON, Cardona A, Ransohoff RM, Lamb BT. Regulation of tau pathology by the microglial fractalkine receptor. Neuron 68(1): 19-31. (2010).
[http://dx.doi.org/10.1016/j.neuron.2010.08.023] [PMID: 20920788]
[141]
Maphis N, Xu G, Kokiko-Cochran ON, Jiang S, Cardona A, Ransohoff RM, et al. Reactive microglia drive tau pathology and contribute to the spreading of pathological tau in the brain. Brain 138(Pt 6): 1738-55. (2015).
[http://dx.doi.org/10.1093/brain/awv081] [PMID: 25833819]
[142]
Stancu IC, Cremers N, Vanrusselt H, Couturier J, Vanoosthuyse A, Kessels S, et al. Aggregated Tau activates NLRP3-ASC inflammasome exacerbating exogenously seeded and non-exogenously seeded Tau pathology in vivo. Acta Neuropathol 137(4): 599-617. (2019).
[http://dx.doi.org/10.1007/s00401-018-01957-y] [PMID: 30721409]
[143]
Ising C, Venegas C, Zhang S, Scheiblich H, Schmidt SV, Vieira-Saecker A, et al. NLRP3 inflammasome activation drives tau pathology. Nature 575(7784): 669-73. (2019).
[http://dx.doi.org/10.1038/s41586-019-1769-z] [PMID: 31748742]
[144]
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 562(7728): 578-82. (2018).
[http://dx.doi.org/10.1038/s41586-018-0543-y] [PMID: 30232451]
[145]
Fuhrmann M, Bittner T, Jung CK, Burgold S, Page RM, Mitteregger G, et al. Microglial Cx3cr1 knockout prevents neuron loss in a mouse model of Alzheimer’s disease. Nat Neurosci 13(4): 411-3. (2010).
[http://dx.doi.org/10.1038/nn.2511] [PMID: 20305648]
[146]
Spangenberg EE, Lee RJ, Najafi AR, Rice RA, Elmore MR, Blurton-Jones M, et al. Eliminating microglia in Alzheimer’s mice prevents neuronal loss without modulating amyloid-β pathology. Brain 139(Pt 4): 1265-81. (2016).
[http://dx.doi.org/10.1093/brain/aww016] [PMID: 26921617]
[147]
Hickman S, Izzy S, Sen P, Morsett L, El Khoury J. Microglia in neurodegeneration. Nat Neurosci 21(10): 1359-69. (2018).
[http://dx.doi.org/10.1038/s41593-018-0242-x] [PMID: 30258234]
[148]
Dejanovic B, Huntley MA, De Mazière A, Meilandt WJ, Wu T, Srinivasan K, et al. Changes in the Synaptic Proteome in Tauopathy and Rescue of Tau-Induced Synapse Loss by C1q Antibodies. Neuron 100(6): 1322-1336.e7. (2018).
[http://dx.doi.org/10.1016/j.neuron.2018.10.014] [PMID: 30392797]
[149]
Liddelow SA, Guttenplan KA, Clarke LE, Bennett FC, Bohlen CJ, Schirmer L, et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature 541(7638): 481-7. (2017).
[http://dx.doi.org/10.1038/nature21029] [PMID: 28099414]
[150]
Lian H, Yang L, Cole A, Sun L, Chiang AC, Fowler SW, et al. NFκB-activated astroglial release of complement C3 compromises neuronal morphology and function associated with Alzheimer’s disease. Neuron 85(1): 101-15. (2015).
[http://dx.doi.org/10.1016/j.neuron.2014.11.018] [PMID: 25533482]
[151]
Lian H, Litvinchuk A, Chiang AC, Aithmitti N, Jankowsky JL, Zheng H. Astrocyte-microglia cross talk through complement activation modulates amyloid pathology in mouse models of Alzheimer’s disease. J Neurosci 36(2): 577-89. (2016).
[http://dx.doi.org/10.1523/JNEUROSCI.2117-15.2016] [PMID: 26758846]
[152]
Litvinchuk A, Wan YW, Swartzlander DB, Chen F, Cole A, Propson NE, et al. Complement C3aR inactivation attenuates tau pathology and reverses an immune network deregulated in tauopathy models and Alzheimer’s disease. Neuron 100(6): 1337-1353.e5. (2018).
[http://dx.doi.org/10.1016/j.neuron.2018.10.031] [PMID: 30415998]
[153]
Merlini M, Rafalski VA, Rios Coronado PE, Gill TM, Ellisman M, Muthukumar G, et al. Fibrinogen induces microglia-mediated spine elimination and cognitive impairment in an Alzheimer’s disease model. Neuron 101(6): 1099-1108.e6. (2019).
[http://dx.doi.org/10.1016/j.neuron.2019.01.014] [PMID: 30737131]
[154]
Paolicelli RC, Jawaid A, Henstridge CM, Valeri A, Merlini M, Robinson JL, et al. TDP-43 depletion in microglia promotes amyloid clearance but also induces synapse loss. Neuron 95(2): 297-308.e6. (2017).
[http://dx.doi.org/10.1016/j.neuron.2017.05.037] [PMID: 28669544]

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