Alzheimer's Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation.
Aged
Aged, 80 and over
Alzheimer Disease
/ genetics
Animals
Cellular Senescence
/ genetics
Databases, Genetic
Female
Frontal Lobe
/ pathology
Frozen Sections
Gene Expression Profiling
Genetic Predisposition to Disease
Heterografts
Humans
Male
Mice
Microglia
/ metabolism
Monocytes
/ metabolism
Multiple Sclerosis
/ pathology
Phenotype
Reproducibility of Results
Risk Factors
Temporal Lobe
/ pathology
Transcriptional Activation
/ genetics
Alzheimer’s disease
aging
microglia
neurodegenerative diseases
neuroinflammation
transcriptomics
Journal
Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691
Informations de publication
Date de publication:
30 06 2020
30 06 2020
Historique:
received:
09
01
2020
revised:
22
04
2020
accepted:
10
06
2020
entrez:
2
7
2020
pubmed:
2
7
2020
medline:
29
4
2021
Statut:
ppublish
Résumé
Damage-associated microglia (DAM) profiles observed in Alzheimer's disease (AD)-related mouse models reflect an activation state that could modulate AD risk or progression. To learn whether human AD microglia (HAM) display a similar profile, we develop a method for purifying cell types from frozen cerebrocortical tissues for RNA-seq analysis, allowing better transcriptome coverage than typical single-nucleus RNA-seq approaches. The HAM profile we observe bears little resemblance to the DAM profile. Instead, HAM display an enhanced human aging profile, in addition to other disease-related changes such as APOE upregulation. Analyses of whole-tissue RNA-seq and single-cell/nucleus RNA-seq datasets corroborate our findings and suggest that the lack of DAM response in human microglia occurs specifically in AD tissues, not other neurodegenerative settings. These results, which can be browsed at http://research-pub.gene.com/BrainMyeloidLandscape, provide a genome-wide picture of microglial activation in human AD and highlight considerable differences between mouse models and human disease.
Identifiants
pubmed: 32610143
pii: S2211-1247(20)30824-X
doi: 10.1016/j.celrep.2020.107843
pmc: PMC7422733
mid: NIHMS1608497
pii:
doi:
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
107843Subventions
Organisme : NIA NIH HHS
ID : P30 AG019610
Pays : United States
Organisme : NINDS NIH HHS
ID : U24 NS072026
Pays : United States
Informations de copyright
Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Interests T.G.B. and G.E.S. participated in this study under a contracted research agreement. All other authors are current or former employees of the pharmaceutical company Genentech, Inc..
Références
Transl Psychiatry. 2018 May 18;8(1):99
pubmed: 29777097
Nature. 2019 Jun;570(7761):332-337
pubmed: 31042697
Immunity. 2017 Sep 19;47(3):566-581.e9
pubmed: 28930663
J Cell Biol. 2018 Feb 5;217(2):459-472
pubmed: 29196460
Curr Opin Neurobiol. 2020 Apr;61:40-48
pubmed: 31863938
Acta Neuropathol. 2009 Oct;118(4):475-85
pubmed: 19513731
Nature. 2019 Feb;566(7744):388-392
pubmed: 30760929
Nat Genet. 2011 May;43(5):436-41
pubmed: 21460841
Neurobiol Aging. 2014 Dec;35(12):2746-2760
pubmed: 25002035
Hum Mutat. 2016 Jan;37(1):16-27
pubmed: 26462614
Nat Genet. 2013 Dec;45(12):1452-8
pubmed: 24162737
Cell. 2017 Jun 15;169(7):1276-1290.e17
pubmed: 28602351
Neurology. 1991 Apr;41(4):479-86
pubmed: 2011243
Neuropathology. 2015 Aug;35(4):354-89
pubmed: 25619230
Acta Neuropathol. 1991;82(4):239-59
pubmed: 1759558
Nat Neurosci. 2016 Mar;19(3):504-16
pubmed: 26780511
Front Aging Neurosci. 2016 Jun 17;8:145
pubmed: 27378917
Cell. 2018 May 17;173(5):1073-1081
pubmed: 29775591
Nat Genet. 2011 May;43(5):429-35
pubmed: 21460840
Circ Res. 2018 Jun 8;122(12):1661-1674
pubmed: 29545365
Cell. 2015 Mar 12;160(6):1061-71
pubmed: 25728668
Brain. 2015 Oct;138(Pt 10):3076-88
pubmed: 26268530
Nat Commun. 2018 Feb 7;9(1):539
pubmed: 29416036
Nat Genet. 2017 Sep;49(9):1373-1384
pubmed: 28714976
Nature. 2019 Feb;566(7745):543-547
pubmed: 30747918
Acta Neuropathol Commun. 2015 May 23;3:31
pubmed: 26001565
Brain. 2006 Dec;129(Pt 12):3315-28
pubmed: 16984899
Cell Discov. 2017 Mar 28;3:17005
pubmed: 28377822
Cell Rep. 2018 Jan 16;22(3):832-847
pubmed: 29346778
Neuron. 2016 Jan 6;89(1):37-53
pubmed: 26687838
Science. 2017 Jun 23;356(6344):
pubmed: 28546318
Nat Neurosci. 2015 Jul;18(7):965-77
pubmed: 26030851
Neuron. 2020 Mar 4;105(5):837-854.e9
pubmed: 31902528
Alzheimers Dement (Amst). 2018 Aug 30;10:706-716
pubmed: 30511008
Cell. 2014 Dec 4;159(6):1312-26
pubmed: 25480296
Neuron. 2019 Sep 25;103(6):1016-1033.e10
pubmed: 31375314
Nat Neurosci. 2017 Aug;20(8):1052-1061
pubmed: 28628103
Nat Genet. 2019 Mar;51(3):414-430
pubmed: 30820047
Nat Commun. 2016 Apr 21;7:11295
pubmed: 27097852
Alzheimers Res Ther. 2019 Aug 9;11(1):71
pubmed: 31399126
Nat Genet. 2019 Mar;51(3):404-413
pubmed: 30617256
J Clin Invest. 2015 May;125(5):2161-70
pubmed: 25893602
Sci Data. 2018 Aug 07;5:180142
pubmed: 30084846
PLoS Genet. 2018 Nov 2;14(11):e1007427
pubmed: 30388101
Nat Neurosci. 2017 Aug;20(8):1162-1171
pubmed: 28671693
Circ Res. 2018 Oct 26;123(10):1127-1142
pubmed: 30359200