Type-I-interferon signaling drives microglial dysfunction and senescence in human iPSC models of Down syndrome and Alzheimer's disease.
Alzheimer's disease
Down syndrome
human induced pluripotent stem cells
microglia
senescence
synaptic pruning
type I interferon
Journal
Cell stem cell
ISSN: 1875-9777
Titre abrégé: Cell Stem Cell
Pays: United States
ID NLM: 101311472
Informations de publication
Date de publication:
07 07 2022
07 07 2022
Historique:
received:
25
11
2021
revised:
27
04
2022
accepted:
09
06
2022
entrez:
8
7
2022
pubmed:
9
7
2022
medline:
14
7
2022
Statut:
ppublish
Résumé
Microglia are critical in brain development and Alzheimer's disease (AD) etiology. Down syndrome (DS) is the most common genetic developmental disorder and risk factor for AD. Surprisingly, little information is available on the impact of trisomy of human chromosome 21 (Hsa21) on microglial functions during DS brain development and in AD in DS. Using induced pluripotent stem cell (iPSC)-based organoid and chimeric mouse models, we report that DS microglia exhibit an enhanced synaptic pruning function, which alters neuronal synaptic functions. In response to human brain tissue-derived pathological tau, DS microglia undergo cellular senescence and exhibit elevated type-I-interferon signaling. Mechanistically, knockdown of Hsa21-encoded type I interferon receptors, IFNARs, rescues the DS microglial phenotypes both during brain development and in response to pathological tau. Our findings provide in vivo evidence that human microglia respond to pathological tau by exhibiting dystrophic phenotypes. Targeting IFNARs may improve DS microglial functions and prevent senescence.
Identifiants
pubmed: 35803230
pii: S1934-5909(22)00256-9
doi: 10.1016/j.stem.2022.06.007
pmc: PMC9345168
mid: NIHMS1816618
pii:
doi:
Substances chimiques
Amyloid beta-Peptides
0
Interferons
9008-11-1
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
1135-1153.e8Subventions
Organisme : NINDS NIH HHS
ID : R01 NS102382
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG073779
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS122108
Pays : United States
Organisme : NIA NIH HHS
ID : P30 AG066519
Pays : United States
Organisme : NIA NIH HHS
ID : U19 AG068054
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2022 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests The authors declare no competing interests.
Références
J Neuropathol Exp Neurol. 1997 Mar;56(3):285-90
pubmed: 9056542
Cell Rep. 2021 Jun 8;35(10):109228
pubmed: 34107254
J Alzheimers Dis. 2017;56(2):459-470
pubmed: 27983553
Cells. 2019 Jul 06;8(7):
pubmed: 31284597
Nat Rev Neurosci. 2018 Oct;19(10):622-635
pubmed: 30206328
Cell Stem Cell. 2019 Jun 6;24(6):908-926.e8
pubmed: 31130512
Trends Neurosci. 2014 Mar;37(3):125-35
pubmed: 24388427
Mol Neurodegener. 2019 Mar 5;14(1):12
pubmed: 30832693
Aging Cell. 2015 Jun;14(3):491-5
pubmed: 25678027
J Neural Transm (Vienna). 2018 May;125(5):797-807
pubmed: 28676934
Glia. 2020 Apr;68(4):845-854
pubmed: 31922322
Nat Immunol. 2019 Apr;20(4):493-502
pubmed: 30833792
Cell. 2017 Jun 15;169(7):1276-1290.e17
pubmed: 28602351
Nat Commun. 2020 Mar 27;11(1):1577
pubmed: 32221280
Cell Rep. 2015 May 5;11(5):785-797
pubmed: 25921537
Cell. 2013 Jun 6;153(6):1194-217
pubmed: 23746838
Nat Neurosci. 2017 May;20(5):753-759
pubmed: 28253233
Clin Immunol Immunopathol. 1996 Mar;78(3):209-14
pubmed: 8605695
Immunity. 2022 May 10;55(5):879-894.e6
pubmed: 35443157
Cell. 2018 May 17;173(5):1073-1081
pubmed: 29775591
Trends Neurosci. 2021 Sep;44(9):714-727
pubmed: 34366147
Acta Neuropathol. 2015 Feb;129(2):221-37
pubmed: 25534024
Nature. 2019 Nov;575(7784):669-673
pubmed: 31748742
J Neurosci. 2008 Nov 5;28(45):11650-61
pubmed: 18987201
Trends Neurosci. 2019 May;42(5):310-322
pubmed: 31006494
Cold Spring Harb Perspect Biol. 2020 Aug 3;12(8):
pubmed: 31767649
Proc Natl Acad Sci U S A. 2019 Nov 26;116(48):24231-24241
pubmed: 31699819
Oncotarget. 2016 Feb 2;7(5):5118-30
pubmed: 26802028
Dis Model Mech. 2011 Sep;4(5):596-606
pubmed: 21816951
Annu Rev Neurosci. 2022 Jul 8;45:425-445
pubmed: 35436413
Glia. 2017 Sep;65(9):1397-1406
pubmed: 28519900
J Clin Invest. 2017 Sep 1;127(9):3220-3229
pubmed: 28758903
J Virol. 2012 May;86(10):5422-36
pubmed: 22398282
Cell Rep. 2019 Nov 12;29(7):1893-1908.e4
pubmed: 31722205
Front Behav Neurosci. 2015 Oct 13;9:268
pubmed: 26528151
Science. 2016 May 6;352(6286):712-716
pubmed: 27033548
Behav Genet. 2006 May;36(3):405-15
pubmed: 16485178
Immunity. 2017 Sep 19;47(3):566-581.e9
pubmed: 28930663
Cell Rep. 2020 May 19;31(7):107666
pubmed: 32433975
Cell Stem Cell. 2013 Mar 7;12(3):342-53
pubmed: 23472873
Glia. 2007 Aug 1;55(10):1074-84
pubmed: 17551926
Acta Neuropathol. 2011 Oct;122(4):455-66
pubmed: 21847625
Nat Med. 2015 Aug;21(8):932-7
pubmed: 26147761
Science. 2006 Mar 31;311(5769):1927-32
pubmed: 16574867
Acta Neuropathol. 1999 Apr;97(4):383-92
pubmed: 10208278
Nucleic Acids Res. 2013 Jan;41(Database issue):D1040-6
pubmed: 23203888
Front Aging Neurosci. 2018 Nov 20;10:378
pubmed: 30515090
Neurobiol Aging. 2005 Mar;26(3):383-9
pubmed: 15639317
Front Aging Neurosci. 2018 May 11;10:140
pubmed: 29867449
Neuron. 2017 Apr 19;94(2):278-293.e9
pubmed: 28426964
Nat Commun. 2015 Jan 29;6:6176
pubmed: 25630253
Nature. 2002 Jan 17;415(6869):327-30
pubmed: 11797010
Cell Death Dis. 2016 Jan 14;7:e2053
pubmed: 26775705
Alzheimers Dement (Amst). 2020 Jul 28;12(1):e12070
pubmed: 32782922
J Cell Biol. 2018 Feb 5;217(2):459-472
pubmed: 29196460
Bioinformatics. 2016 Nov 15;32(22):3532-3534
pubmed: 27412086
Neurobiol Dis. 2015 Jan;73:83-95
pubmed: 25220759
Cell Rep. 2018 Jan 16;22(3):832-847
pubmed: 29346778
Dev Cell. 2009 Dec;17(6):800-10
pubmed: 20059950
Cell. 2015 Oct 8;163(2):324-39
pubmed: 26451483
Science. 2017 Jun 23;356(6344):
pubmed: 28546318
J Immunol. 2007 Nov 15;179(10):6494-503
pubmed: 17982038
Nat Med. 2021 Sep;27(9):1592-1599
pubmed: 34446931
J Neuroinflammation. 2018 Sep 18;15(1):269
pubmed: 30227881
Proc Natl Acad Sci U S A. 2019 Dec 10;116(50):25293-25303
pubmed: 31772018
Birth Defects Res A Clin Mol Teratol. 2010 Dec;88(12):1008-16
pubmed: 20878909
Glia. 2019 Nov;67(11):2125-2141
pubmed: 31058364
Nat Rev Immunol. 2018 Apr;18(4):225-242
pubmed: 29151590
Brain. 2020 Dec 1;143(12):3653-3671
pubmed: 33206953
Acta Neuropathol. 2009 Oct;118(4):475-85
pubmed: 19513731
PLoS One. 2015 Jul 31;10(7):e0134861
pubmed: 26230397
Nature. 2018 Oct;562(7728):578-582
pubmed: 30232451
Cancer Res. 2020 Jan 15;80(2):219-233
pubmed: 31551365
Nat Rev Neurol. 2019 Mar;15(3):135-147
pubmed: 30733618
Neuron. 2019 Sep 25;103(6):1016-1033.e10
pubmed: 31375314
Trends Neurosci. 2015 Oct;38(10):659-668
pubmed: 26442698
Brain. 2015 Oct;138(Pt 10):2814-33
pubmed: 26283673
Aging Cell. 2020 Oct;19(10):e13234
pubmed: 32918364
Neurobiol Aging. 2014 May;35(5):1012-23
pubmed: 24262201
J Exp Med. 2021 Sep 6;218(9):
pubmed: 34292312
Stem Cell Reports. 2021 Aug 10;16(8):1923-1937
pubmed: 34297942
Cell. 2019 Oct 3;179(2):312-339
pubmed: 31564456
Acta Neuropathol. 2016 Dec;132(6):897-916
pubmed: 27743026
Cell Rep. 2020 Jun 30;31(13):107843
pubmed: 32610143
Stem Cell Reports. 2018 Apr 10;10(4):1294-1307
pubmed: 29606617
Nat Commun. 2018 Oct 9;9(1):4167
pubmed: 30301888
Acta Neuropathol Commun. 2021 Jan 5;9(1):1
pubmed: 33402227
J Neuropathol Exp Neurol. 1997 Feb;56(2):143-9
pubmed: 9034367
Autism Res. 2014 Aug;7(4):433-41
pubmed: 24664986
Cell. 2019 Dec 12;179(7):1609-1622.e16
pubmed: 31835035
Neuron. 2020 Dec 9;108(5):887-904.e12
pubmed: 33027640
J Neurosci. 2013 Jan 16;33(3):1024-37
pubmed: 23325240
Alzheimers Dement (Amst). 2020 Oct 14;12(1):e12113
pubmed: 33088896
Glia. 2008 Aug 1;56(10):1048-60
pubmed: 18442088
Autism. 2013 Jul;17(4):390-404
pubmed: 22589453
Science. 2020 Feb 7;367(6478):688-694
pubmed: 32029629
Sci Rep. 2019 Dec 6;9(1):18486
pubmed: 31811168
Neurosci Lett. 1995 Apr 14;189(2):73-6
pubmed: 7609922
Neurobiol Aging. 2021 Mar;99:19-27
pubmed: 33422891
Neurotoxicology. 2011 Mar;32(2):215-26
pubmed: 21112353
Nat Commun. 2014 Jul 18;5:4430
pubmed: 25034944
Glia. 2004 Jan 15;45(2):208-12
pubmed: 14730714
Cell. 2019 Jan 10;176(1-2):334-347.e12
pubmed: 30580966
Stem Cell Reports. 2017 Jun 6;8(6):1727-1742
pubmed: 28591653
Nat Neurosci. 2017 Aug;20(8):1162-1171
pubmed: 28671693
Cell Stem Cell. 2020 May 7;26(5):629-631
pubmed: 32386554
Science. 2016 Apr 22;352(6284):453-9
pubmed: 27102483
Neurobiol Aging. 2017 May;53:36-47
pubmed: 28208064
Genome Biol. 2020 Apr 7;21(1):91
pubmed: 32264951
J Neuropathol Exp Neurol. 2003 Sep;62(9):917-26
pubmed: 14533781
Elife. 2016 Jul 29;5:
pubmed: 27472900