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Neuroimmune contributions to Alzheimer’s disease: a focus on human data
Yancik R, Ershler W, Satariano W, Hazzard W, Cohen HJ, Ferrucci L. Report of the national institute on aging task force on comorbidity. J Gerontol A Biol Sci Med Sci. 2007;62:275–80.
Divo MJ, Martinez CH, Mannino DM. Ageing and the epidemiology of multimorbidity. Eur Respir J. 2014;44:1055–68.
Klein H-U, Trumpff C, Yang H-S, Lee AJ, Picard M, Bennett DA, et al. Characterization of mitochondrial DNA quantity and quality in the human aged and Alzheimer’s disease brain. Molecular. Neurodegeneration. 2021;16:75.
Chornenkyy Y, Fardo DW, Nelson PT. Tau and TDP-43 proteinopathies: kindred pathologic cascades and genetic pleiotropy. Lab Investig. 2019;99:993–1007.
Visanji NP, Lang AE, Kovacs GG. Beyond the synucleinopathies: alpha synuclein as a driving force in neurodegenerative comorbidities. Transl Neurodegener. 2019;8:28.
Moussaud S, Jones DR, Moussaud-Lamodière EL, Delenclos M, Ross OA, McLean PJ. Alpha-synuclein and tau: teammates in neurodegeneration? Mol Neurodegener. 2014;9:43.
Yang HS, White CC, Klein HU, Yu L, Gaiteri C, Ma Y, et al. Genetics of gene expression in the aging human brain reveal TDP-43 proteinopathy pathophysiology. Neuron. 2020;107:496–508.e496.
Rabin JS, Yang HS, Schultz AP, Hanseeuw BJ, Hedden T, Viswanathan A, et al. Vascular risk and β-amyloid are synergistically associated with cortical tau. Ann Neurol. 2019;85:272–9.
Alzheimer A, Stelzmann RA, Schnitzlein HN, Murtagh FR. An English translation of Alzheimer’s 1907 paper, “Uber eine eigenartige Erkankung der Hirnrinde”. Clin Anat. 1995;8:429–31.
Möller HJ, Graeber MB. The case described by Alois Alzheimer in 1911. Historical and conceptual perspectives based on the clinical record and neurohistological sections. Eur Arch Psychiatry Clin Neurosci. 1998;248:111–22.
yCajal SR. Contribucion al conocimiento de la neuroglia del cerebro humano, 1913.
Del Rıo Hortega P. El ‘tercer elemento’de los centros nerviosos. I. La microglıa en estado normal. Bol Soc Esp Biol. 1920;8:68–92.
Sierra A, Paolicelli RC, Kettenmann H. Cien Anos de microbial: milestones in a century of microbial research. Trends Neurosci. 2019;42:778–92.
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.
Rogers J, Luber-Narod J, Styren SD, Civin WH. Expression of immune system-associated antigens by cells of the human central nervous system: Relationship to the pathology of Alzheimer’s disease. Neurobiol Aging. 1988;9:339–49.
Sue W, Griffin T, Stanley LC, Ling C, White L, MacLeod V, et al. Brain interleukin 1 and S-100 immunoreactivity are elevated in Down syndrome and Alzheimer disease. Proc Natl Acad Sci USA. 1989;86:7611–5.
Guerreiro R, Wojtas A, Bras J, Carrasquillo M, Rogaeva E, Majounie E, et al. TREM2 variants in Alzheimer’s disease. N Engl J Med. 2013;368:117–27.
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. 2013;368:107–16.
Hollingworth P, Harold D, Sims R, Gerrish A, Lambert JC, Carrasquillo MM, et al. Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer’s disease. Nat Genet. 2011;43:429–35.
Lambert JC, Grenier-Boley B, Chouraki V, Heath S, Zelenika D, Fievet N, et al. Implication of the immune system in Alzheimer’s disease: evidence from genome-wide pathway analysis. J Alzheimer’s Dis. 2010;20:1107–18.
Raj T, Rothamel K, Mostafavi S, Ye C, Lee MN, Replogle JM, et al. Polarization of the effects of autoimmune and neurodegenerative risk alleles in leukocytes. Science. 2014;344:519–23.
Zhang B, Gaiteri C, Bodea LG, Wang Z, McElwee J, Podtelezhnikov AA, et al. Integrated systems approach identifies genetic nodes and networks in late-onset Alzheimer’s disease. Cell. 2013;153:707–20.
Jones L, Holmans PA, Hamshere ML, Harold D, Moskvina V, Ivanov D, et al. Genetic evidence implicates the immune system and cholesterol metabolism in the aetiology of Alzheimer’s disease. PLoS One. 2010;5:e13950.
Wes PD, Sayed FA, Bard F, Gan L. Targeting microglia for the treatment of Alzheimer’s disease. Glia. 2016;64:1710–32.
Sims R, van der Lee SJ, Naj AC, Bellenguez C, Badarinarayan N, Jakobsdottir J, et al. Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer’s disease. Nat Genet. 2017;49:1373–84.
Bettens K, Brouwers N, Engelborghs S, De Deyn PP, Van Broeckhoven C, Sleegers K. SORL1 is genetically associated with increased risk for late-onset Alzheimer disease in the Belgian population. Hum Mutat. 2008;29:769–70.
Pottier C, Hannequin D, Coutant S, Rovelet-Lecrux A, Wallon D, Rousseau S, et al. High frequency of potentially pathogenic SORL1 mutations in autosomal dominant early-onset Alzheimer disease. Mol Psychiatry. 2012;17:875–9.
Cruchaga C, Karch CM, Jin SC, Benitez BA, Cai Y, Guerreiro R, et al. Rare coding variants in the phospholipase D3 gene confer risk for Alzheimer’s disease. Nature. 2014;505:550–4.
Liao X, Cai F, Sun Z, Zhang Y, Wang J, Jiao B, et al. Identification of Alzheimer’s disease-associated rare coding variants in the ECE2 gene. JCI Insight. 2020;5:e135119.
International Multiple Sclerosis Genetics Consortium. Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility. Science. 2019;365:eaav7188.
Felsky D, Patrick E, Schneider JA, Mostafavi S, Gaiteri C, Patsopoulos N, et al. Polygenic analysis of inflammatory disease variants and effects on microglia in the aging brain. Mol Neurodegener. 2018;13:38.
Bradshaw EM, Chibnik LB, Keenan BT, Ottoboni L, Raj T, Tang A, et al. CD33 Alzheimer’s disease locus: altered monocyte function and amyloid biology. Nat Neurosci. 2013;16:848–50.
Replogle JM, Chan G, White CC, Raj T, Winn PA, Evans DA, et al. A TREM1 variant alters the accumulation of Alzheimer-related amyloid pathology. Ann Neurol. 2015;77:469–77.
Kleineidam L, Chouraki V, Próchnicki T, van der Lee SJ, Madrid-Márquez L, Wagner-Thelen H, et al. PLCG2 protective variant p.P522R modulates tau pathology and disease progression in patients with mild cognitive impairment. Acta Neuropathol. 2020;139:1025–44.
Liu C, Yu J. Genome-wide association studies for cerebrospinal fluid soluble TREM2 in Alzheimer’s disease. Front Aging Neurosci. 2019;11:297.
Chan G, White CC, Winn PA, Cimpean M, Replogle JM, Glick LR, et al. CD33 modulates TREM2: convergence of Alzheimer loci. Nat Neurosci. 2015;18:1556–8.
Huang K-l, Marcora E, Pimenova AA, Di Narzo AF, Kapoor M, Jin SC, et al. A common haplotype lowers PU.1 expression in myeloid cells and delays onset of Alzheimer’s disease. Nat Neurosci. 2017;20:1052–61.
Raj T, Shulman JM, Keenan BT, Chibnik LB, Evans DA, Bennett DA, et al. Alzheimer disease susceptibility loci: evidence for a protein network under natural selection. Am J Hum Genet. 2012;90:720–6.
Ní Chasaide C, Lynch MA. The role of the immune system in driving neuroinflammation. Brain Neurosci Adv. 2020;4:2398212819901082.
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. 2018;48:380–.e386.
Thome AD, Faridar A, Beers DR, Thonhoff JR, Zhao W, Wen S, et al. Functional alterations of myeloid cells during the course of Alzheimer’s disease. Mol Neurodegener. 2018;13:61.
Chen S-H, Tian D-Y, Shen Y-Y, Cheng Y, Fan D-Y, Sun H-L, et al. Amyloid-beta uptake by blood monocytes is reduced with ageing and Alzheimer’s disease. Transl Psychiatry. 2020;10:423.
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. 2017;20:1162–71.
Mathys H, Davila-Velderrain J, Peng Z, Gao F, Mohammadi S, Young JZ, et al. Single-cell transcriptomic analysis of Alzheimer’s disease. Nature. 2019;570:332–7.
Olah M, Menon V, Habib N, Taga MF, Ma Y, Yung CJ, et al. Single cell RNA sequencing of human microglia uncovers a subset associated with Alzheimer’s disease. Nat Commun. 2020;11:6129.
Naert G, Rivest S. CC chemokine receptor 2 deficiency aggravates cognitive impairments and amyloid pathology in a transgenic mouse model of Alzheimer’s disease. J Neurosci. 2011;31:6208–20.
El Khoury J, Toft M, Hickman SE, Means TK, Terada K, Geula C, et al. Ccr2 deficiency impairs microglial accumulation and accelerates progression of Alzheimer-like disease. Nat Med. 2007;13:432–8.
Yamamoto M, Horiba M, Buescher JL, Huang D, Gendelman HE, Ransohoff RM, et al. Overexpression of monocyte chemotactic protein-1/CCL2 in beta-amyloid precursor protein transgenic mice show accelerated diffuse beta-amyloid deposition. Am J Pathol. 2005;166:1475–85.
Unger MS, Schernthaner P, Marschallinger J, Mrowetz H, Aigner L. Microglia prevent peripheral immune cell invasion and promote an anti-inflammatory environment in the brain of APP-PS1 transgenic mice. J Neuroinflammation. 2018;15:274.
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. 2017;37:637–47.
Shukla AK, McIntyre LL, Marsh SE, Schneider CA, Hoover EM, Walsh CM, et al. CD11a expression distinguishes infiltrating myeloid cells from plaque-associated microglia in Alzheimer’s disease. Glia. 2019;67:844–56.
Simard AR, Rivest S. Bone marrow stem cells have the ability to populate the entire central nervous system into fully differentiated parenchymal microglia. Faseb j. 2004;18:998–1000.
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. 2006;49:489–502.
Stalder AK, Ermini F, Bondolfi L, Krenger W, Burbach GJ, Deller T, et al. Invasion of hematopoietic cells into the brain of amyloid precursor protein transgenic mice. J Neurosci. 2005;25:11125–32.
Chen Z, Feng X, Herting CJ, Garcia VA, Nie K, Pong WW, et al. Cellular and molecular identity of tumor-associated macrophages in glioblastoma. Cancer Res. 2017;77:2266–78.
Kelly RJ, Minogue AM, Lyons A, Jones RS, Browne TC, Costello DA, et al. Glial activation in AβPP/PS1 mice is associated with infiltration of IFNγ-producing cells. J Alzheimer’s Dis. 2013;37:63–75.
Minogue AM, Jones RS, Kelly RJ, McDonald CL, Connor TJ, Lynch MA. Age-associated dysregulation of microglial activation is coupled with enhanced blood-brain barrier permeability and pathology in APP/PS1 mice. Neurobiol Aging. 2014;35:1442–52.
Itagaki S, McGeer PL, Akiyama H. Presence of T-cytotoxic suppressor and leucocyte common antigen positive cells in Alzheimer’s disease brain tissue. Neurosci Lett. 1988;91:259–64.
Togo T, Akiyama H, Iseki E, Kondo H, Ikeda K, Kato M, et al. Occurrence of T cells in the brain of Alzheimer’s disease and other neurological diseases. J Neuroimmunol. 2002;124:83–92.
Gate D, Saligrama N, Leventhal O, Yang AC, Unger MS, Middeldorp J, et al. Clonally expanded CD8 T cells patrol the cerebrospinal fluid in Alzheimer’s disease. Nature. 2020;577:399–404.
Busse M, Michler E, von Hoff F, Dobrowolny H, Hartig R, Frodl T, et al. Alterations in the peripheral immune system in dementia. J Alzheimer’s Dis. 2017;58:1303–13.
Dhanwani R, Pham J, Premlal ALR, Frazier A, Kumar A, Pero ME, et al. T cell responses to neural autoantigens are similar in Alzheimer’s disease patients and age-matched healthy controls. Front Neurosci. 2020;14:874.
Merlini M, Kirabali T, Kulic L, Nitsch RM, Ferretti MT. Extravascular CD3+ T cells in brains of alzheimer disease patients correlate with tau but not with amyloid pathology: an immunohistochemical study. Neurodegener Dis. 2018;18:49–56.
Unger MS, Li E, Scharnagl L, Poupardin R, Altendorfer B, Mrowetz H, et al. CD8+ T-cells infiltrate Alzheimer’s disease brains and regulate neuronal- and synapse-related gene expression in APP-PS1 transgenic mice. Brain, Behav, Immun. 2020;89:67–86.
Richartz-Salzburger E, Batra A, Stransky E, Laske C, Köhler N, Bartels M, et al. Altered lymphocyte distribution in Alzheimer’s disease. J Psychiatr Res. 2007;41:174–8.
Pellicanò M, Larbi A, Goldeck D, Colonna-Romano G, Buffa S, Bulati M, et al. Immune profiling of Alzheimer patients. J Neuroimmunol. 2012;242:52–59.
Leal-Lasarte M, Mannini B, Chiti F, Vendruscolo M, Dobson CM, Roodveldt C, et al. Distinct responses of human peripheral blood cells to different misfolded protein oligomers. Immunology. 2021;164:358–71.
Ciccocioppo F, Lanuti P, Pierdomenico L, Simeone P, Bologna G, Ercolino E, et al. The characterization of regulatory T-cell profiles in Alzheimer’s disease and multiple sclerosis. Sci Rep. 2019;9:8788.
Larbi A, Pawelec G, Witkowski JM, Schipper HM, Derhovanessian E, Goldeck D, et al. Dramatic shifts in circulating CD4 but not CD8 T cell subsets in mild Alzheimer’s disease. J Alzheimer’s Dis. 2009;17:91–103.
Dansokho C, Ait Ahmed D, Aid S, Toly-Ndour C, Chaigneau T, Calle V, et al. Regulatory T cells delay disease progression in Alzheimer-like pathology. Brain. 2016;139:1237–51.
Faridar A, Thome AD, Zhao W, Thonhoff JR, Beers DR, Pascual B, et al. Restoring regulatory T-cell dysfunction in Alzheimer’s disease through ex vivo expansion. Brain Commun. 2020;2:fcaa112.
Giubilei F, Antonini G, Montesperelli C, Sepe-Monti M, Cannoni S, Pichi A, et al. T cell response to amyloid-beta and to mitochondrial antigens in Alzheimer’s disease. Dement Geriatr Cogn Disord. 2003;16:35–38.
Monsonego A, Zota V, Karni A, Krieger JI, Bar-Or A, Bitan G, et al. Increased T cell reactivity to amyloid beta protein in older humans and patients with Alzheimer disease. J Clin Investig. 2003;112:415–22.
Oberstein TJ, Taha L, Spitzer P, Hellstern J, Herrmann M, Kornhuber J, et al. Imbalance of circulating Th17 and regulatory T cells in Alzheimer’s disease: a case control study. Front Immunol. 2018;9:1213.
Aliseychik M, Patrikeev A, Gusev F, Grigorenko A, Andreeva T, Biragyn A, et al. Dissection of the human T-cell receptor γ gene repertoire in the brain and peripheral blood identifies age- and Alzheimer’s disease-associated clonotype profiles. Front Immunol. 2020;11:12.
Lutshumba J, Nikolajczyk BS, Bachstetter AD. Dysregulation of systemic immunity in aging and dementia. Front Cell Neurosci. 2021;15:652111.
Da Mesquita S, Fu Z, Kipnis J. The meningeal lymphatic system: a new player in neurophysiology. Neuron. 2018;100:375–88.
Benveniste H, Liu X, Koundal S, Sanggaard S, Lee H, Wardlaw J. The glymphatic system and waste clearance with brain aging: a review. Gerontology. 2019;65:106–19.
Iliff JJ, Wang M, Liao Y, Plogg BA, Peng W, Gundersen GA, et al. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β. Sci Transl Med. 2012;4:147ra111–147ra111.
Iliff JJ, Wang M, Zeppenfeld DM, Venkataraman A, Plog BA, Liao Y, et al. Cerebral arterial pulsation drives paravascular CSF–interstitial fluid exchange in the murine brain. J Neurosci. 2013;33:18190–9.
Da Mesquita S, Louveau A, Vaccari A, Smirnov I, Cornelison RC, Kingsmore KM, et al. Functional aspects of meningeal lymphatics in ageing and Alzheimer’s disease. Nature. 2018;560:185–91.
Mentis A-FA, Dardiotis E, Chrousos GP. Apolipoprotein E4 and meningeal lymphatics in Alzheimer disease: a conceptual framework. Mol Psychiatry. 2021;26:1075–97.
Ransohoff RM, Engelhardt B. The anatomical and cellular basis of immune surveillance in the central nervous system. Nat Rev Immunol. 2012;12:623–35.
Wardlaw JM, Benveniste H, Nedergaard M, Zlokovic BV, Mestre H, Lee H, et al. Perivascular spaces in the brain: anatomy, physiology and pathology. Nat Rev Neurol. 2020;16:137–53.
Yang T, Guo R, Zhang F. Brain perivascular macrophages: Recent advances and implications in health and diseases. CNS Neurosci Ther. 2019;25:1318–28.
Hawkes CA, McLaurin J. Selective targeting of perivascular macrophages for clearance of beta-amyloid in cerebral amyloid angiopathy. Proc Natl Acad Sci USA. 2009;106:1261–6.
Thanopoulou K, Fragkouli A, Stylianopoulou F, Georgopoulos S. Scavenger receptor class B type I (SR-BI) regulates perivascular macrophages and modifies amyloid pathology in an Alzheimer mouse model. Proc Natl Acad Sci USA. 2010;107:20816–21.
Park L, Uekawa K, Garcia-Bonilla L, Koizumi K, Murphy M, Pistik R, et al. Brain perivascular macrophages initiate the neurovascular dysfunction of Alzheimer Aβ peptides. Circ Res. 2017;121:258–69.
Zenaro E, Piacentino G, Constantin G. The blood-brain barrier in Alzheimer’s disease. Neurobiol Dis. 2017;107:41–56.
Lau S-F, Cao H, Fu AKY, Ip NY. Single-nucleus transcriptome analysis reveals dysregulation of angiogenic endothelial cells and neuroprotective glia in Alzheimer’s disease. Proc Natl Acad Sci. 2020;117:25800–9.
Dulken BW, Buckley MT, Navarro Negredo P, Saligrama N, Cayrol R, Leeman DS, et al. Single-cell analysis reveals T cell infiltration in old neurogenic niches. Nature. 2019;571:205–10.
Ferreira IL, Resende R, Ferreiro E, Rego AC, Pereira CF. Multiple defects in energy metabolism in Alzheimer’s disease. Curr Drug Targets. 2010;11:1193–206.
Deane R, Singh I, Sagare AP, Bell RD, Ross NT, LaRue B, et al. A multimodal RAGE-specific inhibitor reduces amyloid β-mediated brain disorder in a mouse model of Alzheimer disease. J Clin Investig. 2012;122:1377–92.
Pflanzner T, Kuhlmann CR, Pietrzik CU. Blood-brain-barrier models for the investigation of transporter- and receptor-mediated amyloid-β clearance in Alzheimer’s disease. Curr Alzheimer Res. 2010;7:578–90.
Sagare AP, Bell RD, Zlokovic BV. Neurovascular dysfunction and faulty amyloid β-peptide clearance in Alzheimer disease. Cold Spring Harb Perspect Med. 2012;2:a011452.
Donahue JE, Flaherty SL, Johanson CE, Duncan JA, Silverberg GD, Miller MC, et al. RAGE, LRP-1, and amyloid-beta protein in Alzheimer’s disease. Acta Neuropathol. 2006;112:405–15.
Oikari LE, Pandit R, Stewart R, Cuní-López C, Quek H, Sutharsan R, et al. Altered brain endothelial cell phenotype from a familial alzheimer mutation and its potential implications for amyloid clearance and drug delivery. Stem Cell Rep. 2020;14:924–39.
Cain A, Taga M, McCabe C, Hekselman I, White CC, Green G, et al. Multi-cellular communities are perturbed in the aging human brain and with Alzheimer’s disease. bioRxiv 2020: 2020.2012.2022.424084.
Ponath G, Park C, Pitt D. The role of astrocytes in multiple sclerosis. Front Immunol. 2018;9:217.
Priego N, Valiente M. The potential of astrocytes as immune modulators in brain tumors. Front Immunol. 2019;10:1314.
Sofroniew MV, Vinters HV. Astrocytes: biology and pathology. Acta Neuropathol. 2010;119:7–35.
Medeiros R, LaFerla FM. Astrocytes: conductors of the Alzheimer disease neuroinflammatory symphony. Exp Neurol. 2013;239:133–8.
Olabarria M, Noristani HN, Verkhratsky A, Rodríguez JJ. Concomitant astroglial atrophy and astrogliosis in a triple transgenic animal model of Alzheimer’s disease. Glia. 2010;58:831–8.
Verkhratsky A, Rodrigues JJ, Pivoriunas A, Zorec R, Semyanov A. Astroglial atrophy in Alzheimer’s disease. Pflug Arch. 2019;471:1247–61.
Heneka MT, Carson MJ, Khoury JE, Landreth GE, Brosseron F, Feinstein DL, et al. Neuroinflammation in Alzheimer’s disease. Lancet Neurol. 2015;14:388–405.
Seyfried NT, Dammer EB, Swarup V, Nandakumar D, Duong DM, Yin L, et al. A multi-network approach identifies protein-specific co-expression in asymptomatic and symptomatic Alzheimer’s disease. Cell Syst. 2017;4:60–72.e64.
Wan YW, Al-Ouran R, Mangleburg CG, Perumal TM, Lee TV, Allison K, et al. Meta-analysis of the Alzheimer’s disease human brain transcriptome and functional dissection in mouse models. Cell Rep. 2020;32:107908.
Patrick E, Olah M, Taga M, Klein HU, Xu J, White CC, et al. A cortical immune network map identifies distinct microglial transcriptional programs associated with beta-amyloid and Tau pathologies. Transl Psychiatry. 2021;11:50.
Colonna M, Wang Y. TREM2 variants: new keys to decipher Alzheimer disease pathogenesis. Nat Rev Neurosci. 2016;17:201–7.
Kleinberger G, Brendel M, Mracsko E, Wefers B, Groeneweg L, Xiang X, et al. The FTD-like syndrome causing TREM2 T66M mutation impairs microglia function, brain perfusion, and glucose metabolism. Embo J. 2017;36:1837–53.
Deming Y, Filipello F, Cignarella F, Cantoni C, Hsu S, Mikesell R, et al. The MS4A gene cluster is a key modulator of soluble TREM2 and Alzheimer’s disease risk. Sci Transl Med. 2019;11:eaau2291.
Piers TM, Cosker K, Mallach A, Johnson GT, Guerreiro R, Hardy J, et al. A locked immunometabolic switch underlies TREM2 R47H loss of function in human iPSC-derived microglia. FASEB j. 2020;34:2436–50.
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. 2015;290:26043–50.
Salter MW, Stevens B. Microglia emerge as central players in brain disease. Nat Med. 2017;23:1018–27.
Rangaraju S, Dammer EB, Raza SA, Gao T, Xiao H, Betarbet R, et al. Quantitative proteomics of acutely-isolated mouse microglia identifies novel immune Alzheimer’s disease-related proteins. Mol Neurodegener. 2018;13:34.
Olah M, Patrick E, Villani A-C, Xu J, White CC, Ryan KJ, et al. A transcriptomic atlas of aged human microglia. Nat Commun. 2018;9:539.
Fernandez CG, Hamby ME, McReynolds ML, Ray WJ. The role of APOE4 in disrupting the homeostatic functions of astrocytes and microglia in aging and Alzheimer’s disease. Front Aging Neurosci. 2019;11:14.
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. 2013;78:631–43.
Jun G, Naj AC, Beecham GW, Wang LS, Buros J, Gallins PJ, et al. Meta-analysis confirms CR1, CLU, and PICALM as alzheimer disease risk loci and reveals interactions with APOE genotypes. Arch Neurol. 2010;67:1473–84.
Andreone BJ, Przybyla L, Llapashtica C, Rana A, Davis SS, van Lengerich B, et al. Alzheimer’s-associated PLCγ2 is a signaling node required for both TREM2 function and the inflammatory response in human microglia. Nat Neurosci. 2020;23:927–38.
Stewart CR, Stuart LM, Wilkinson K, van Gils JM, Deng J, Halle A, et al. CD36 ligands promote sterile inflammation through assembly of a Toll-like receptor 4 and 6 heterodimer. Nat Immunol. 2010;11:155–61.
Sheedy FJ, Grebe A, Rayner KJ, Kalantari P, Ramkhelawon B, Carpenter SB, et al. CD36 coordinates NLRP3 inflammasome activation by facilitating intracellular nucleation of soluble ligands into particulate ligands in sterile inflammation. Nat Immunol. 2013;14:812–20.
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. 2003;197:1657–66.
Hoeijmakers L, Heinen Y, van Dam A-M, Lucassen PJ, Korosi A. Microglial priming and Alzheimer’s disease: a possible role for (early) immune challenges and epigenetics? Front Hum Neurosci. 2016;10:398–398.
Neher JJ, Cunningham C. Priming microglia for innate immune memory in the brain. Trends Immunol. 2019;40:358–74.
Perry VH, Cunningham C, Holmes C. Systemic infections and inflammation affect chronic neurodegeneration. Nat Rev Immunol. 2007;7:161–7.
Galloway DA, Phillips AEM, Owen DRJ, Moore CS. Phagocytosis in the brain: homeostasis and disease. Front Immunol. 2019;10:790.
Felsky D, Roostaei T, Nho K, Risacher SL, Bradshaw EM, Petyuk V, et al. Neuropathological correlates and genetic architecture of microglial activation in elderly human brain. Nat Commun. 2019;10:409.
Vogels T, Murgoci A-N, Hromádka T. Intersection of pathological tau and microglia at the synapse. Acta Neuropathol Commun. 2019;7:109.
Rexach JE, Polioudakis D, Yin A, Swarup V, Chang TS, Nguyen T, et al. Tau pathology drives dementia risk-associated gene networks toward chronic inflammatory states and immunosuppression. Cell Rep. 2020;33:108398.
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. 2017;169:1276–.e1217.
Rozemuller JM, Eikelenboom P, Pals ST, Stam FC. Microglial cells around amyloid plaques in Alzheimer’s disease express leucocyte adhesion molecules of the LFA-1 family. Neurosci Lett. 1989;101:288–92.
Dionisio-Santos DA, Olschowka JA, O’Banion MK. Exploiting microglial and peripheral immune cell crosstalk to treat Alzheimer’s disease. J Neuroinflammation. 2019;16:74.
Bauer J, Strauss S, Schreiter-Gasser U, Ganter U, Schlegel P, Witt I, et al. Interleukin-6 and alpha-2-macroglobulin indicate an acute-phase state in Alzheimer’s disease cortices. FEBS Lett. 1991;285:111–4.
Park JC, Han SH, Mook-Jung I. Peripheral inflammatory biomarkers in Alzheimer’s disease: a brief review. BMB Rep. 2020;53:10–19.
Anoop A, Singh PK, Jacob RS, Maji SK. CSF biomarkers for alzheimer’s disease diagnosis. Int J Alzheimer’s Dis. 2010;2010:606802.
Wu Y-Y, Hsu J-L, Wang H-C, Wu S-J, Hong C-J, Cheng IH-J. Alterations of the neuroinflammatory markers IL-6 and TRAIL in Alzheimer’s disease. Dement Geriatr Cogn Dis Extra. 2015;5:424–34.
Eriksson UK, Pedersen NL, Reynolds CA, Hong MG, Prince JA, Gatz M, et al. Associations of gene sequence variation and serum levels of C-reactive protein and interleukin-6 with Alzheimer’s disease and dementia. J Alzheimer’s Dis. 2011;23:361–9.
Ng A, Tam WW, Zhang MW, Ho CS, Husain SF, McIntyre RS, et al. IL-1β, IL-6, TNF- α and CRP in elderly patients with depression or Alzheimer’s disease: systematic review and meta-analysis. Sci Rep. 2018;8:12050.
Locascio JJ, Fukumoto H, Yap L, Bottiglieri T, Growdon JH, Hyman BT, et al. Plasma amyloid beta-protein and C-reactive protein in relation to the rate of progression of Alzheimer disease. Arch Neurol. 2008;65:776–85.
Watanabe Y, Kitamura K, Nakamura K, Sanpei K, Wakasugi M, Yokoseki A, et al. Elevated C-reactive protein is associated with cognitive decline in outpatients of a general hospital: the Project in Sado for Total Health (PROST). Dement Geriatr Cogn Dis Extra. 2016;6:10–19.
Vintimilla R, Hall J, Johnson L, O’Bryant S. The relationship of CRP and cognition in cognitively normal older Mexican Americans: a cross-sectional study of the HABLE cohort. Medicines. 2019;98:e15605.
Yarchoan M, Louneva N, Xie SX, Swenson FJ, Hu W, Soares H, et al. Association of plasma C-reactive protein levels with the diagnosis of Alzheimer’s disease. J Neurol Sci. 2013;333:9–12.
Sjogren T, Sjogren H, Lindgren AG. Morbus Alzheimer and morbus Pick; a genetic, clinical and patho-anatomical study. Acta Psychiatr Neurol Scand Suppl. 1952;82:1–152.
Itzhaki RF, Lathe R, Balin BJ, Ball MJ, Bearer EL, Braak H, et al. Microbes and Alzheimer’s disease. J Alzheimer’s Dis. 2016;51:979–84.
Mastroeni D, Nolz J, Sekar S, Delvaux E, Serrano G, Cuyugan L, et al. Laser-captured microglia in the Alzheimer’s and Parkinson’s brain reveal unique regional expression profiles and suggest a potential role for hepatitis B in the Alzheimer’s brain. Neurobiol Aging. 2018;63:12–21.
Kountouras J, Boziki M, Gavalas E, Zavos C, Deretzi G, Grigoriadis N, et al. Increased cerebrospinal fluid Helicobacter pylori antibody in Alzheimer’s disease. Int J Neurosci. 2009;119:765–77.
Sochocka M, Zwolińska K, Leszek J. The infectious etiology of Alzheimer’s disease. Curr Neuropharmacol. 2017;15:996–1009.
Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, Cole GM, et al. Inflammation and Alzheimer’s disease. Neurobiol Aging. 2000;21:383–421.
Soscia SJ, Kirby JE, Washicosky KJ, Tucker SM, Ingelsson M, Hyman B, et al. The Alzheimer’s disease-associated amyloid beta-protein is an antimicrobial peptide. PLoS One. 2010;5:e9505.
Kumar DK, Choi SH, Washicosky KJ, Eimer WA, Tucker S, Ghofrani J, et al. Amyloid-β peptide protects against microbial infection in mouse and worm models of Alzheimer’s disease. Sci Transl Med. 2016;8:340ra372.
Eimer WA, Vijaya Kumar DK, Navalpur Shanmugam NK, Rodriguez AS, Mitchell T, Washicosky KJ, et al. Alzheimer’s disease-associated β-amyloid is rapidly seeded by herpesviridae to protect against brain infection. Neuron. 2018;99:56–63.e53.
Itzhaki RF. Corroboration of a major role for Herpes simplex virus type 1 in Alzheimer’s disease. Front Aging Neurosci. 2018;10:324.
Readhead B, Haure-Mirande JV, Funk CC, Richards MA, Shannon P, Haroutunian V, et al. Multiscale analysis of independent Alzheimer’s cohorts finds disruption of molecular, genetic, and clinical networks by human herpesvirus. Neuron. 2018;99:64–82.e67.
Allnutt MA, Johnson K, Bennett DA, Connor SM, Troncoso JC, Pletnikova O, et al. Human herpesvirus 6 detection in Alzheimer’s disease cases and controls across multiple cohorts. Neuron. 2020;105:1027–.e1022.
Seaks CE, Wilcock DM. Infectious hypothesis of Alzheimer disease. PLoS Pathog. 2020;16:e1008596–e1008596.
Balin BJ, Hammond CJ, Little CS, Hingley ST, Al-Atrache Z, Appelt DM, et al. Chlamydia pneumoniae: an etiologic agent for late-onset dementia. Front Aging Neurosci. 2018;10:302.
Singhrao SK, Olsen I. Assessing the role of Porphyromonas gingivalis in periodontitis to determine a causative relationship with Alzheimer’s disease. J Oral Microbiol. 2019;11:1563405.
Abbayya K, Puthanakar NY, Naduwinmani S, Chidambar YS. Association between Periodontitis and Alzheimer’s disease. North Am J Med Sci. 2015;7:241–6.
Lauc G, Sinclair D. Biomarkers of biological age as predictors of COVID-19 disease severity. Aging. 2020;12:6490–1.
Fang L, Karakiulakis G, Roth M. Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection? Lancet Respir Med. 2020;8:e21–e21.
Hu B, Huang S, Yin L. The cytokine storm and COVID-19. J Med Virol. 2021;93:250–6.
Rea IM, Gibson DS, McGilligan V, McNerlan SE, Alexander HD, Ross OA. Age and age-related diseases: role of inflammation triggers and cytokines. Front Immunol. 2018;9:586.
Qin C, Zhou L, Hu Z, Zhang S, Yang S, Tao Y, et al. Dysregulation of immune response in patients with coronavirus 2019 (COVID-19) in Wuhan, China. Clin Infect Dis. 2020;71:762–8.
Naughton SX, Raval U, Pasinetti GM. Potential novel role of COVID-19 in Alzheimer’s disease and preventative mitigation strategies. J Alzheimer’s Dis. 2020;76:21–25.
Matschke J, Lütgehetmann M, Hagel C, Sperhake JP, Schröder AS, Edler C, et al. Neuropathology of patients with COVID-19 in Germany: a post-mortem case series. Lancet Neurol. 2020;19:919–29.
Meinhardt J, Radke J, Dittmayer C, Franz J, Thomas C, Mothes R, et al. Olfactory transmucosal SARS-CoV-2 invasion as a port of central nervous system entry in individuals with COVID-19. Nat Neurosci. 2021;24:168–75.
Taquet M, Geddes JR, Husain M, Luciano S, Harrison PJ. 6-month neurological and psychiatric outcomes in 236 379 survivors of COVID-19: a retrospective cohort study using electronic health records. Lancet Psychiatry. 2021;8:416–27.
Huang C, Huang L, Wang Y, Li X, Ren L, Gu X, et al. 6-month consequences of COVID-19 in patients discharged from hospital: a cohort study. Lancet. 2021;397:220–32.
Nalbandian A, Sehgal K, Gupta A, Madhavan MV, McGroder C, Stevens JS, et al. Post-acute COVID-19 syndrome. Nat Med. 2021;27:601–15.
Whitmer RA, Gustafson DR, Barrett-Connor E, Haan MN, Gunderson EP, Yaffe K. Central obesity and increased risk of dementia more than three decades later. Neurology. 2008;71:1057–64.
Walker JM, Harrison FE. Shared neuropathological characteristics of obesity, type 2 diabetes and Alzheimer’s disease: impacts on cognitive decline. Nutrients. 2015;7:7332–57.
Li JQ, Tan L, Wang HF, Tan MS, Tan L, Xu W, et al. Risk factors for predicting progression from mild cognitive impairment to Alzheimer’s disease: a systematic review and meta-analysis of cohort studies. J Neurol Neurosurg Psychiatry. 2016;87:476–84.
Arvanitakis Z, Wilson RS, Bienias JL, Evans DA, Bennett DA. Diabetes mellitus and risk of Alzheimer disease and decline in cognitive function. Arch Neurol. 2004;61:661–6.
Farris W, Mansourian S, Chang Y, Lindsley L, Eckman EA, Frosch MP, et al. Insulin-degrading enzyme regulates the levels of insulin, amyloid beta-protein, and the beta-amyloid precursor protein intracellular domain in vivo. Proc Natl Acad Sci USA. 2003;100:4162–7.
Newcombe EA, Camats-Perna J, Silva ML, Valmas N, Huat TJ, Medeiros R. Inflammation: the link between comorbidities, genetics, and Alzheimer’s disease. J Neuroinflammation. 2018;15:276.
Luchsinger JA, Gustafson DR. Adiposity, type 2 diabetes, and Alzheimer’s disease. J Alzheimer’s Dis. 2009;16:693–704.
Lukic L, Lalic NM, Rajkovic N, Jotic A, Lalic K, Milicic T, et al. Hypertension in obese type 2 diabetes patients is associated with increases in insulin resistance and IL-6 cytokine levels: potential targets for an efficient preventive intervention. Int J Environ Res Public Health. 2014;11:3586–98.
Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW Jr. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Investig. 2003;112:1796–808.
Cortez M, Carmo LS, Rogero MM, Borelli P, Fock RA. A high-fat diet increases IL-1, IL-6, and TNF-α production by increasing NF-κB and attenuating PPAR-γ expression in bone marrow mesenchymal stem cells. Inflammation. 2013;36:379–86.
Kempuraj D, Thangavel R, Selvakumar GP, Zaheer S, Ahmed ME, Raikwar SP, et al. Brain and peripheral atypical inflammatory mediators potentiate neuroinflammation and neurodegeneration. Front Cell Neurosci. 2017;11:216.
Carabotti M, Scirocco A, Maselli MA, Severi C. The gut-brain axis: interactions between enteric microbiota, central and enteric nervous systems. Ann Gastroenterol. 2015;28:203–9.
Friedland RP, Chapman MR. The role of microbial amyloid in neurodegeneration. PLoS Pathog. 2017;13:e1006654.
Le Chatelier E, Nielsen T, Qin J, Prifti E, Hildebrand F, Falony G, et al. Richness of human gut microbiome correlates with metabolic markers. Nature. 2013;500:541–6.
Askarova S, Umbayev B, Masoud A-R, Kaiyrlykyzy A, Safarova Y, Tsoy A, et al. The links between the gut microbiome, aging, modern lifestyle and Alzheimer’s disease. Front Cell Infection Microbiol. 2020;10:104.
Strandwitz P. Neurotransmitter modulation by the gut microbiota. Brain Res. 2018;1693:128–33.
Cattaneo A, Cattane N, Galluzzi S, Provasi S, Lopizzo N, Festari C, et al. Association of brain amyloidosis with pro-inflammatory gut bacterial taxa and peripheral inflammation markers in cognitively impaired elderly. Neurobiol Aging. 2017;49:60–68.
Brandscheid C, Schuck F, Reinhardt S, Schäfer KH, Pietrzik CU, Grimm M, et al. Altered gut microbiome composition and tryptic activity of the 5xFAD Alzheimer’s mouse model. J Alzheimer’s Dis. 2017;56:775–88.
Vogt NM, Kerby RL, Dill-McFarland KA, Harding SJ, Merluzzi AP, Johnson SC, et al. Gut microbiome alterations in Alzheimer’s disease. Sci Rep. 2017;7:13537.
Barrett E, Ross RP, O’Toole PW, Fitzgerald GF, Stanton C. γ-Aminobutyric acid production by culturable bacteria from the human intestine. J Appl Microbiol. 2012;113:411–7.
Harach T, Marungruang N, Duthilleul N, Cheatham V, Mc Coy KD, Frisoni G, et al. Reduction of Abeta amyloid pathology in APPPS1 transgenic mice in the absence of gut microbiota. Sci Rep. 2017;7:41802.
Chapman MR, Robinson LS, Pinkner JS, Roth R, Heuser J, Hammar M, et al. Role of Escherichia coli curli operons in directing amyloid fiber formation. Science. 2002;295:851–5.
Zhang R, Miller RG, Gascon R, Champion S, Katz J, Lancero M, et al. Circulating endotoxin and systemic immune activation in sporadic amyotrophic lateral sclerosis (sALS). J Neuroimmunol. 2009;206:121–4.
Erny D, Hrabě de Angelis AL, Jaitin D, Wieghofer P, Staszewski O, David E, et al. Host microbiota constantly control maturation and function of microglia in the CNS. Nat Neurosci. 2015;18:965–77.
Rampelli S, Candela M, Turroni S, Biagi E, Collino S, Franceschi C, et al. Functional metagenomic profiling of intestinal microbiome in extreme ageing. Aging. 2013;5:902–12.
Fung TC, Olson CA, Hsiao EY. Interactions between the microbiota, immune and nervous systems in health and disease. Nat Neurosci. 2017;20:145–55.
Scott KA, Ida M, Peterson VL, Prenderville JA, Moloney GM, Izumo T, et al. Revisiting Metchnikoff: age-related alterations in microbiota-gut-brain axis in the mouse. Brain Behav Immun. 2017;65:20–32.
Ferretti MT, Iulita MF, Cavedo E, Chiesa PA, Schumacher Dimech A, Santuccione, et al. Sex differences in Alzheimer disease – the gateway to precision medicine. Nat Rev Neurol. 2018;14:457–69.
Mazure CM, Swendsen J. Sex differences in Alzheimer’s disease and other dementias. Lancet Neurol. 2016;15:451–2.
Seshadri S, Wolf PA, Beiser A, Au R, McNulty K, White R, et al. Lifetime risk of dementia and Alzheimer’s disease. The impact of mortality on risk estimates in the Framingham study. Neurology. 1997;49:1498–504.
Plassman BL, Langa KM, McCammon RJ, Fisher GG, Potter GG, Burke JR, et al. Incidence of dementia and cognitive impairment, not dementia in the United States. Ann Neurol. 2011;70:418–26.
Dubal DB. Sex difference in Alzheimer’s disease: an updated, balanced and emerging perspective on differing vulnerabilities. Handb Clin Neurol. 2020;175:261–73.
Ossenkoppele R, Lyoo CH, Jester-Broms J, Sudre CH, Cho H, Ryu YH, et al. Assessment of demographic, genetic, and imaging variables associated with brain resilience and cognitive resilience to pathological tau in patients With Alzheimer disease. JAMA Neurol. 2020;77:632–42.
Nebel RA, Aggarwal NT, Barnes LL, Gallagher A, Goldstein JM, Kantarci K, et al. Understanding the impact of sex and gender in Alzheimer’s disease: a call to action. Alzheimer’s Dement. 2018;14:1171–83.
Tang AS, Oskotsky T, Havaldar S, Mantyh WG, Bicak M, Solsberg CW, et al. Deep phenotyping of Alzheimer’s disease leveraging electronic medical records identifies sex-specific clinical associations. Nat Commun. 2022;13:675.
Bove R, Secor E, Chibnik LB, Barnes LL, Schneider JA, Bennett DA, et al. Age at surgical menopause influences cognitive decline and Alzheimer pathology in older women. Neurology. 2014;82:222–9.
Corder E, Saunders A, Strittmatter W, Schmechel D, Gaskell P, Small G, et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science. 1993;261:921–3.
Saunders AM, Strittmatter WJ, Schmechel D, St. George-Hyslop PH, Pericak-Vance MA, Joo SH, et al. Association of apolipoprotein E allele ϵ4 with late‐onset familial and sporadic Alzheimer’s disease. Neurology. 1993;43:1467–1467.
Strittmatter WJ, Saunders AM, Schmechel D, Pericak-Vance M, Enghild J, Salvesen GS, et al. Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci. 1993;90:1977–81.
Mosconi L, Berti V, Quinn C, McHugh P, Petrongolo G, Osorio RS, et al. Perimenopause and emergence of an Alzheimer’s bioenergetic phenotype in brain and periphery. PLoS One. 2017;12:e0185926.
Neu SC, Pa J, Kukull W, Beekly D, Kuzma A, Gangadharan P, et al. Apolipoprotein E genotype and sex risk factors for Alzheimer disease: a meta-analysis. JAMA Neurol. 2017;74:1178–89.
Guillot-Sestier M-V, Araiz AR, Mela V, Gaban AS, O’Neill E, Joshi L, et al. Microglial metabolism is a pivotal factor in sexual dimorphism in Alzheimer’s disease. Commun Biol. 2021;4:711.
Yanguas-Casás N. Physiological sex differences in microglia and their relevance in neurological disorders. Neuroimmunol Neuroinflammation. 2020;7:13–22.
Villa A, Gelosa P, Castiglioni L, Cimino M, Rizzi N, Pepe G, et al. Sex-specific features of microglia from adult mice. Cell Rep. 2018;23:3501–11.
Sierra A, Gottfried-Blackmore A, Milner TA, McEwen BS, Bulloch K. Steroid hormone receptor expression and function in microglia. Glia. 2008;56:659–74.
Sárvári M, Hrabovszky E, Kalló I, Solymosi N, Likó I, Berchtold N, et al. Menopause leads to elevated expression of macrophage-associated genes in the aging frontal cortex: rat and human studies identify strikingly similar changes. J Neuroinflammation. 2012;9:264.
Hanamsagar R, Alter MD, Block CS, Sullivan H, Bolton JL, Bilbo SD. Generation of a microglial developmental index in mice and in humans reveals a sex difference in maturation and immune reactivity. Glia. 2017;65:1504–20.
Villa A, Vegeto E, Poletti A, Maggi A. Estrogens, neuroinflammation, and neurodegeneration. Endocr Rev. 2016;37:372–402.
Schwarz JM, Sholar PW, Bilbo SD. Sex differences in microglial colonization of the developing rat brain. J Neurochem. 2012;120:948–63.
Guneykaya D, Ivanov A, Hernandez DP, Haage V, Wojtas B, Meyer N, et al. Transcriptional and translational differences of microglia from male and female brains. Cell Rep. 2018;24:2773–.e2776.
Goronzy JJ, Weyand CM. Understanding immunosenescence to improve responses to vaccines. Nat Immunol. 2013;14:428–36.
Parisi MM, Grun LK, Lavandoski P, Alves LB, Bristot IJ, Mattiello R, et al. Immunosenescence induced by plasma from individuals with obesity caused cell signaling dysfunction and inflammation. Obesity. 2017;25:1523–31.
Chiu Y-L, Tsai W-C, Hung R-W, Chen IY, Shu K-H, Pan S-Y, et al. Emergence of T cell immunosenescence in diabetic chronic kidney disease. Immun Ageing. 2020;17:31.
Fulop T, Larbi A, Dupuis G, Le Page A, Frost EH, Cohen AA, et al. Immunosenescence and inflamm-aging as two sides of the same coin: friends or foes? Front Immunol. 2018;8:1960.
Thomas S, Rouilly V, Patin E, Alanio C, Dubois A, Delval C, et al. The Milieu Intérieur study—an integrative approach for study of human immunological variance. Clin Immunol. 2015;157:277–93.
Márquez EJ, Chung C-H, Marches R, Rossi RJ, Nehar-Belaid D, Eroglu A, et al. Sexual-dimorphism in human immune system aging. Nat Commun. 2020;11:751.
Zhou Y, Song WM, Andhey PS, Swain A, Levy T, Miller KR, et al. Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and TREM2-independent cellular responses in Alzheimer’s disease. Nat Med. 2020;26:131–42.
Sankowski R, Bottcher C, Masuda T, Geirsdottir L, Sagar, Sindram E, et al. Mapping microglia states in the human brain through the integration of high-dimensional techniques. Nat Neurosci. 2019;22:2098–110.
Miller KR, Streit WJ. The effects of aging, injury and disease on microglial function: a case for cellular senescence. Neuron Glia Biol. 2007;3:245–53.
Streit WJ, Sammons NW, Kuhns AJ, Sparks DL. Dystrophic microglia in the aging human brain. Glia. 2004;45:208–12.
Davies DS, Ma J, Jegathees T, Goldsbury C. Microglia show altered morphology and reduced arborization in human brain during aging and Alzheimer’s disease. Brain Pathol. 2017;27:795–808.
Wong WT. Microglial aging in the healthy CNS: phenotypes, drivers, and rejuvenation. Front Cell Neurosci. 2013;7:22–22.
Njie EG, Boelen E, Stassen FR, Steinbusch HW, Borchelt DR, Streit WJ. Ex vivo cultures of microglia from young and aged rodent brain reveal age-related changes in microglial function. Neurobiol Aging. 2012;33:195.e191–112.
Hickman SE, Allison EK, El Khoury J. Microglial dysfunction and defective beta-amyloid clearance pathways in aging Alzheimer’s disease mice. J Neurosci. 2008;28:8354–60.
Grabert K, Michoel T, Karavolos MH, Clohisey S, Baillie JK, Stevens MP, et al. Microglial brain region−dependent diversity and selective regional sensitivities to aging. Nat Neurosci. 2016;19:504–16.
Bhat R, Crowe EP, Bitto A, Moh M, Katsetos CD, Garcia FU, et al. Astrocyte senescence as a component of Alzheimer’s disease. PLoS One. 2012;7:e45069.
Clarke LE, Liddelow SA, Chakraborty C, Münch AE, Heiman M, Barres BA. Normal aging induces A1-like astrocyte reactivity. Proc Natl Acad Sci USA. 2018;115:E1896–E1905.
Rodríguez-Arellano JJ, Parpura V, Zorec R, Verkhratsky A. Astrocytes in physiological aging and Alzheimer’s disease. Neuroscience. 2016;323:170–82.
Park J, Wetzel I, Marriott I, Dréau D, D’Avanzo C, Kim DY, et al. A 3D human triculture system modeling neurodegeneration and neuroinflammation in Alzheimer’s disease. Nat Neurosci. 2018;21:941–51.
Choi SH, Kim YH, Hebisch M, Sliwinski C, Lee S, D’Avanzo C, et al. A three-dimensional human neural cell culture model of Alzheimer’s disease. Nature. 2014;515:274–8.
Arber C, Lovejoy C, Wray S. Stem cell models of Alzheimer’s disease: progress and challenges. Alzheimer’s Res Ther. 2017;9:42.
Ryan KJ, White CC, Patel K, Xu J, Olah M, Replogle JM, et al. A human microglia-like cellular model for assessing the effects of neurodegenerative disease gene variants. Sci Transl Med. 2017;9:eaai7635.
Sellgren CM, Sheridan SD, Gracias J, Xuan D, Fu T, Perlis RH. Patient-specific models of microglia-mediated engulfment of synapses and neural progenitors. Mol Psychiatry. 2017;22:170–7.
Banerjee A, Lu Y, Do K, Mize T, Wu X, Chen X, et al. Validation of induced microglia-like cells (iMG Cells) for future studies of brain diseases. Front Cell Neurosci. 2021;15:629279.
Abud EM, Ramirez RN, Martinez ES, Healy LM, Nguyen CHH, Newman SA, et al. iPSC-Derived human microglia-like cells to study neurological diseases. Neuron. 2017;94:278–.e279.
Muffat J, Li Y, Yuan B, Mitalipova M, Omer A, Corcoran S, et al. Efficient derivation of microglia-like cells from human pluripotent stem cells. Nat Med. 2016;22:1358–67.
Pandya H, Shen MJ, Ichikawa DM, Sedlock AB, Choi Y, Johnson KR, et al. Differentiation of human and murine induced pluripotent stem cells to microglia-like cells. Nat Neurosci. 2017;20:753–9.
Xu R, Li X, Boreland AJ, Posyton A, Kwan K, Hart RP, et al. Human iPSC-derived mature microglia retain their identity and functionally integrate in the chimeric mouse brain. Nat Commun. 2020;11:1577.
Svoboda DS, Barrasa MI, Shu J, Rietjens R, Zhang S, Mitalipova M, et al. Human iPSC-derived microglia assume a primary microglia-like state after transplantation into the neonatal mouse brain. Proc Natl Acad Sci. 2019;116:25293–303.
Götz J, Bodea L-G, Goedert M. Rodent models for Alzheimer disease. Nat Rev Neurosci. 2018;19:583–98.
Myers A, McGonigle P. Overview of transgenic mouse models for Alzheimer’s disease. Curr Protoc Neurosci. 2019;89:e81.
Cavaliere C, Tramontano L, Fiorenza D, Alfano V, Aiello M, Salvatore M. Gliosis and neurodegenerative diseases: the role of PET and MR imaging. Front Cell Neurosci. 2020;14:75.
Zou J, Tao S, Johnson A, Tomljanovic Z, Polly K, Klein J, et al. Microglial activation, but not tau pathology, is independently associated with amyloid positivity and memory impairment. Neurobiol Aging. 2020;85:11–21.
Klein J, Yan X, Johnson A, Tomljanovic Z, Zou J, Polly K, et al. Olfactory impairment is related to tau pathology and neuroinflammation in Alzheimer’s disease. J Alzheimer’s Dis. 2021;80:1051–65.
Pereira JB, Janelidze S, Smith R, Mattsson-Carlgren N, Palmqvist S, Teunissen CE, et al. Plasma GFAP is an early marker of amyloid-beta but not tau pathology in Alzheimer’s disease. Brain. 2021;144:3505–16.
Prins S, Zhuparris A, Hart EP, Doll RJ, Groeneveld GJ. A cross-sectional study in healthy elderly subjects aimed at development of an algorithm to increase identification of Alzheimer pathology for the purpose of clinical trial participation. Alzheimer’s Res Ther. 2021;13:132.
Lee JC, Kim SJ, Hong S, Kim Y. Diagnosis of Alzheimer’s disease utilizing amyloid and tau as fluid biomarkers. Exp Mol Med. 2019;51:1–10.
Sevigny J, Chiao P, Bussière T, Weinreb PH, Williams L, Maier M, et al. The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease. Nature. 2016;537:50–56.
Kastanenka KV, Bussiere T, Shakerdge N, Qian F, Weinreb PH, Rhodes K, et al. Immunotherapy with aducanumab restores calcium homeostasis in Tg2576 mice. J Neurosci. 2016;36:12549–58.
Sabbagh MN, Cummings J. Open peer commentary to “Failure to demonstrate efficacy of aducanumab: an analysis of the EMERGE and ENGAGE trials as reported by Biogen December 2019”. Alzheimer’s Dement. 2021;17:702–3.
https://agora.ampadportal.org/genes/(genes-router:genes-list)
Xu Y, Kong J, Hu P. Computational drug repurposing for Alzheimer’s disease using risk genes from GWAS and single-cell RNA sequencing studies. Front Pharmacol. 2021;12:617537.
King EA, Davis JW, Degner JF. Are drug targets with genetic support twice as likely to be approved? Revised estimates of the impact of genetic support for drug mechanisms on the probability of drug approval. PLOS Genet. 2019;15:e1008489.
Heppner FL, Ransohoff RM, Becher B. Immune attack: the role of inflammation in Alzheimer disease. Nat Rev Neurosci. 2015;16:358–72.
Vlad SC, Miller DR, Kowall NW, Felson DT. Protective effects of NSAIDs on the development of Alzheimer disease. Neurology. 2008;70:1672–7.
Zandi PP, Anthony JC, Hayden KM, Mehta K, Mayer L, Breitner JC. Reduced incidence of AD with NSAID but not H2 receptor antagonists: the Cache County Study. Neurology. 2002;59:880–6.
Appleby BS, Nacopoulos D, Milano N, Zhong K, Cummings JL. A review: treatment of Alzheimer’s disease discovered in repurposed agents. Dement Geriatr Cogn Disord. 2013;35:1–22.
McGeer PL, Harada N, Kimura H, McGeer EG, Schulzer M. Prevalence of dementia amongst Elderly Japanese with Leprosy: apparent effect of chronic drug therapy. Dement Geriatr Cogn Disord. 1992;3:146–9.
Policicchio S, Ahmad AN, Powell JF, Proitsi P. Rheumatoid arthritis and risk for Alzheimer’s disease: a systematic review and meta-analysis and a Mendelian Randomization study. Sci Rep. 2017;7:12861.
Vedin I, Cederholm T, Freund Levi Y, Basun H, Garlind A, Faxén Irving G, et al. Effects of docosahexaenoic acid-rich n-3 fatty acid supplementation on cytokine release from blood mononuclear leukocytes: the OmegAD study. Am J Clin Nutr. 2008;87:1616–22.
Chen H, Liu S, Ji L, Wu T, Ji Y, Zhou Y, et al. Folic acid supplementation mitigates Alzheimer’s disease by reducing inflammation: a randomized controlled trial. Mediators Inflamm. 2016;2016:5912146–5912146.
Cerovic M, Forloni G, Balducci C. Neuroinflammation and the gut microbiota: possible alternative therapeutic targets to counteract Alzheimer’s disease? Front Aging Neurosci. 2019;11:284.
Simpkins JW, Perez E, Wang X, Yang S, Wen Y, Singh M. The potential for estrogens in preventing Alzheimer’s disease and vascular dementia. Ther Adv Neurol Disord. 2009;2:31–49.
Sanchez JR, Marsh S, McIntyre L, Davtyan H, Walsh C, Blurton-Jones M. Cytotoxic T cells infiltrate the brain and interact with microglia to reduce Alzheimer’s disease pathogenesis. J Immunol. 2020;204:64.64–64.64.
Mittal K, Eremenko E, Berner O, Elyahu Y, Strominger I, Apelblat D, et al. CD4 T cells induce a subset of MHCII-expressing microglia that attenuates Alzheimer’s pathology. iScience. 2019;16:298–311.
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What Are The Main Benefits Of Comparing Car Insurance Quotes Online
LOS ANGELES, CA / ACCESSWIRE / June 24, 2020, / Compare-autoinsurance.Org has launched a new blog post that presents the main benefits of comparing multiple car insurance quotes. For more info and free online quotes, please visit https://compare-autoinsurance.Org/the-advantages-of-comparing-prices-with-car-insurance-quotes-online/ The modern society has numerous technological advantages. One important advantage is the speed at which information is sent and received. With the help of the internet, the shopping habits of many persons have drastically changed. The car insurance industry hasn't remained untouched by these changes. On the internet, drivers can compare insurance prices and find out which sellers have the best offers. View photos The advantages of comparing online car insurance quotes are the following: Online quotes can be obtained from anywhere and at any time. Unlike physical insurance agencies, websites don't have a specific schedule and they are available at any time. Drivers that have busy working schedules, can compare quotes from anywhere and at any time, even at midnight. Multiple choices. Almost all insurance providers, no matter if they are well-known brands or just local insurers, have an online presence. Online quotes will allow policyholders the chance to discover multiple insurance companies and check their prices. Drivers are no longer required to get quotes from just a few known insurance companies. Also, local and regional insurers can provide lower insurance rates for the same services. Accurate insurance estimates. Online quotes can only be accurate if the customers provide accurate and real info about their car models and driving history. Lying about past driving incidents can make the price estimates to be lower, but when dealing with an insurance company lying to them is useless. Usually, insurance companies will do research about a potential customer before granting him coverage. Online quotes can be sorted easily. Although drivers are recommended to not choose a policy just based on its price, drivers can easily sort quotes by insurance price. Using brokerage websites will allow drivers to get quotes from multiple insurers, thus making the comparison faster and easier. For additional info, money-saving tips, and free car insurance quotes, visit https://compare-autoinsurance.Org/ Compare-autoinsurance.Org is an online provider of life, home, health, and auto insurance quotes. This website is unique because it does not simply stick to one kind of insurance provider, but brings the clients the best deals from many different online insurance carriers. In this way, clients have access to offers from multiple carriers all in one place: this website. On this site, customers have access to quotes for insurance plans from various agencies, such as local or nationwide agencies, brand names insurance companies, etc. "Online quotes can easily help drivers obtain better car insurance deals. All they have to do is to complete an online form with accurate and real info, then compare prices", said Russell Rabichev, Marketing Director of Internet Marketing Company. CONTACT: Company Name: Internet Marketing CompanyPerson for contact Name: Gurgu CPhone Number: (818) 359-3898Email: [email protected]: https://compare-autoinsurance.Org/ SOURCE: Compare-autoinsurance.Org View source version on accesswire.Com:https://www.Accesswire.Com/595055/What-Are-The-Main-Benefits-Of-Comparing-Car-Insurance-Quotes-Online View photos
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