APOE modulates microglial immunometabolism in response to age, amyloid pathology, and inflammatory challenge.
APOE
Apolipoprotein E
CP: Neuroscience
DAM
LPS
aging
amyloid
immunometabolism
microglia
scRNA-seq
spatial transcriptomics
Journal
Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691
Informations de publication
Date de publication:
28 03 2023
28 03 2023
Historique:
received:
08
07
2022
revised:
29
11
2022
accepted:
14
02
2023
medline:
3
4
2023
pubmed:
6
3
2023
entrez:
5
3
2023
Statut:
ppublish
Résumé
The E4 allele of Apolipoprotein E (APOE) is associated with both metabolic dysfunction and a heightened pro-inflammatory response: two findings that may be intrinsically linked through the concept of immunometabolism. Here, we combined bulk, single-cell, and spatial transcriptomics with cell-specific and spatially resolved metabolic analyses in mice expressing human APOE to systematically address the role of APOE across age, neuroinflammation, and AD pathology. RNA sequencing (RNA-seq) highlighted immunometabolic changes across the APOE4 glial transcriptome, specifically in subsets of metabolically distinct microglia enriched in the E4 brain during aging or following an inflammatory challenge. E4 microglia display increased Hif1α expression and a disrupted tricarboxylic acid (TCA) cycle and are inherently pro-glycolytic, while spatial transcriptomics and mass spectrometry imaging highlight an E4-specific response to amyloid that is characterized by widespread alterations in lipid metabolism. Taken together, our findings emphasize a central role for APOE in regulating microglial immunometabolism and provide valuable, interactive resources for discovery and validation research.
Identifiants
pubmed: 36871219
pii: S2211-1247(23)00207-3
doi: 10.1016/j.celrep.2023.112196
pmc: PMC10117631
mid: NIHMS1887279
pii:
doi:
Substances chimiques
Apolipoproteins E
0
Apolipoprotein E4
0
Amyloidogenic Proteins
0
Amyloid beta-Peptides
0
Apolipoprotein E3
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
112196Subventions
Organisme : NIA NIH HHS
ID : T32 AG057461
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG070830
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG062550
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM118292
Pays : United States
Organisme : NIA NIH HHS
ID : F31 AG076282
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG080589
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG066653
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA177558
Pays : United States
Organisme : NINDS NIH HHS
ID : RF1 NS118558
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG060056
Pays : United States
Organisme : NIA NIH HHS
ID : T32 AG078110
Pays : United States
Informations de copyright
Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests The authors declare no competing interests.
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