Absence of microglia promotes diverse pathologies and early lethality in Alzheimer's disease mice.
Alzheimer Disease
/ pathology
Amyloid beta-Peptides
/ metabolism
Animals
Brain
/ metabolism
Cerebral Amyloid Angiopathy
/ complications
Disease Models, Animal
Humans
Induced Pluripotent Stem Cells
Membrane Glycoproteins
Mice
Mice, Transgenic
Microglia
/ metabolism
Plaque, Amyloid
/ pathology
Receptors, Immunologic
Alzheimer’s disease
Alzheimer’s disease co-pathologies
CP: Neuroscience
TREM2
brain calcification
cerebral amyloid angiopathy
hemorrhage
iPSC-microglia
microglia
mortality
neurovascular
Journal
Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691
Informations de publication
Date de publication:
14 06 2022
14 06 2022
Historique:
received:
02
11
2021
revised:
13
04
2022
accepted:
24
05
2022
entrez:
15
6
2022
pubmed:
16
6
2022
medline:
18
6
2022
Statut:
ppublish
Résumé
Microglia are strongly implicated in the development and progression of Alzheimer's disease (AD), yet their impact on pathology and lifespan remains unclear. Here we utilize a CSF1R hypomorphic mouse to generate a model of AD that genetically lacks microglia. The resulting microglial-deficient mice exhibit a profound shift from parenchymal amyloid plaques to cerebral amyloid angiopathy (CAA), which is accompanied by numerous transcriptional changes, greatly increased brain calcification and hemorrhages, and premature lethality. Remarkably, a single injection of wild-type microglia into adult mice repopulates the microglial niche and prevents each of these pathological changes. Taken together, these results indicate the protective functions of microglia in reducing CAA, blood-brain barrier dysfunction, and brain calcification. To further understand the clinical implications of these findings, human AD tissue and iPSC-microglia were examined, providing evidence that microglia phagocytose calcium crystals, and this process is impaired by loss of the AD risk gene, TREM2.
Identifiants
pubmed: 35705056
pii: S2211-1247(22)00743-4
doi: 10.1016/j.celrep.2022.110961
pmc: PMC9285116
mid: NIHMS1816595
pii:
doi:
Substances chimiques
Amyloid beta-Peptides
0
Membrane Glycoproteins
0
Receptors, Immunologic
0
Trem2 protein, mouse
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
110961Subventions
Organisme : NIA NIH HHS
ID : P30 AG066519
Pays : United States
Organisme : NIA NIH HHS
ID : T32 AG073088
Pays : United States
Organisme : NIA NIH HHS
ID : T32 AG000096
Pays : United States
Organisme : NIA NIH HHS
ID : RF1 AG055524
Pays : United States
Organisme : NIDA NIH HHS
ID : RF1 DA048813
Pays : United States
Organisme : NINDS NIH HHS
ID : T32 NS082174
Pays : United States
Organisme : NHLBI NIH HHS
ID : R61 HL154307
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG056303
Pays : United States
Organisme : Medical Research Council
ID : MR/M019969/1
Pays : United Kingdom
Organisme : NIA NIH HHS
ID : R01 AG061895
Pays : United States
Informations de copyright
Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests M.B.-J. is a co-inventor of patent application WO/2018/160496, related to the differentiation of pluripotent stem cells into microglia, and co-founder of NovoGlia. All other authors declare no competing interests.
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