APOE4 drives transcriptional heterogeneity and maladaptive immunometabolic responses of astrocytes.

Autor:	Lee S; Sanders-Brown Center on Aging, University of Kentucky College of Medicine, Lexington, KY., Williams HC; Sanders-Brown Center on Aging, University of Kentucky College of Medicine, Lexington, KY.; Department of Physiology, University of Kentucky College of Medicine, Lexington, KY., Gorman AA; Sanders-Brown Center on Aging, University of Kentucky College of Medicine, Lexington, KY., Devanney NA; Sanders-Brown Center on Aging, University of Kentucky College of Medicine, Lexington, KY.; Department of Biology, University of Kentucky College of Arts and Sciences, Lexington, KY., Harrison DA; Boston University, Chobanian & Avedisian School of Medicine, Boston, MA., Walsh AE; Department of Biology, University of Kentucky College of Arts and Sciences, Lexington, KY., Goulding DS; Sanders-Brown Center on Aging, University of Kentucky College of Medicine, Lexington, KY., Tuck T; Boston University, Chobanian & Avedisian School of Medicine, Boston, MA., Schwartz JL; Sanders-Brown Center on Aging, University of Kentucky College of Medicine, Lexington, KY., Zajac DJ; Sanders-Brown Center on Aging, University of Kentucky College of Medicine, Lexington, KY.; Department of Biology, University of Kentucky College of Arts and Sciences, Lexington, KY., Macauley SL; Department of Physiology and Pharmacology, Wake Forest School of Medicine, Winston-Salem, NC., Estus S; Sanders-Brown Center on Aging, University of Kentucky College of Medicine, Lexington, KY.; Department of Biology, University of Kentucky College of Arts and Sciences, Lexington, KY., Julia T; Boston University, Chobanian & Avedisian School of Medicine, Boston, MA., Johnson LA; Sanders-Brown Center on Aging, University of Kentucky College of Medicine, Lexington, KY.; Department of Biology, University of Kentucky College of Arts and Sciences, Lexington, KY., Morganti JM; Sanders-Brown Center on Aging, University of Kentucky College of Medicine, Lexington, KY.; Department of Neuroscience, University of Kentucky College of Medicine, Lexington, KY.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2023 Feb 06. Date of Electronic Publication: 2023 Feb 06.
DOI:	10.1101/2023.02.06.527204
Abstrakt:	Apolipoprotein E4 (APOE4) is the strongest risk allele associated with the development of late onset Alzheimer's disease (AD). Across the CNS, astrocytes are the predominant expressor of APOE while also being critical mediators of neuroinflammation and cerebral metabolism. APOE4 has been consistently linked with dysfunctional inflammation and metabolic processes, yet insights into the molecular constituents driving these responses remain unclear. Utilizing complementary approaches across humanized APOE mice and isogenic human iPSC astrocytes, we demonstrate that ApoE4 alters the astrocyte immunometabolic response to pro-inflammatory stimuli. Our findings show that ApoE4-expressing astrocytes acquire distinct transcriptional repertoires at single-cell and spatially-resolved domains, which are driven in-part by preferential utilization of the cRel transcription factor. Further, inhibiting cRel translocation in ApoE4 astrocytes abrogates inflammatory-induced glycolytic shifts and in tandem mitigates production of multiple pro-inflammatory cytokines. Altogether, our findings elucidate novel cellular underpinnings by which ApoE4 drives maladaptive immunometabolic responses of astrocytes.
Databáze:	MEDLINE
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