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APOE4 drives transcriptional heterogeneity and maladaptive immunometabolic responses of astrocytes

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 consistentl...

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Autores principales: Lee, Sangderk, Williams, Holden C., Gorman, Amy A., Devanney, Nicholas A., Harrison, Douglas A., Walsh, Adeline E., Goulding, Danielle S., Tuck, Tony, Schwartz, James L., Zajac, Diana J., Macauley, Shannon L., Estus, Steven, Julia, TCW, Johnson, Lance A., Morganti, Josh M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9934552/
https://www.ncbi.nlm.nih.gov/pubmed/36798317
http://dx.doi.org/10.1101/2023.02.06.527204
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author Lee, Sangderk
Williams, Holden C.
Gorman, Amy A.
Devanney, Nicholas A.
Harrison, Douglas A.
Walsh, Adeline E.
Goulding, Danielle S.
Tuck, Tony
Schwartz, James L.
Zajac, Diana J.
Macauley, Shannon L.
Estus, Steven
Julia, TCW
Johnson, Lance A.
Morganti, Josh M.
author_facet Lee, Sangderk
Williams, Holden C.
Gorman, Amy A.
Devanney, Nicholas A.
Harrison, Douglas A.
Walsh, Adeline E.
Goulding, Danielle S.
Tuck, Tony
Schwartz, James L.
Zajac, Diana J.
Macauley, Shannon L.
Estus, Steven
Julia, TCW
Johnson, Lance A.
Morganti, Josh M.
author_sort Lee, Sangderk
collection PubMed
description 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.
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spelling pubmed-99345522023-02-17 APOE4 drives transcriptional heterogeneity and maladaptive immunometabolic responses of astrocytes Lee, Sangderk Williams, Holden C. Gorman, Amy A. Devanney, Nicholas A. Harrison, Douglas A. Walsh, Adeline E. Goulding, Danielle S. Tuck, Tony Schwartz, James L. Zajac, Diana J. Macauley, Shannon L. Estus, Steven Julia, TCW Johnson, Lance A. Morganti, Josh M. bioRxiv Article 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. Cold Spring Harbor Laboratory 2023-02-06 /pmc/articles/PMC9934552/ /pubmed/36798317 http://dx.doi.org/10.1101/2023.02.06.527204 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator.
spellingShingle Article
Lee, Sangderk
Williams, Holden C.
Gorman, Amy A.
Devanney, Nicholas A.
Harrison, Douglas A.
Walsh, Adeline E.
Goulding, Danielle S.
Tuck, Tony
Schwartz, James L.
Zajac, Diana J.
Macauley, Shannon L.
Estus, Steven
Julia, TCW
Johnson, Lance A.
Morganti, Josh M.
APOE4 drives transcriptional heterogeneity and maladaptive immunometabolic responses of astrocytes
title APOE4 drives transcriptional heterogeneity and maladaptive immunometabolic responses of astrocytes
title_full APOE4 drives transcriptional heterogeneity and maladaptive immunometabolic responses of astrocytes
title_fullStr APOE4 drives transcriptional heterogeneity and maladaptive immunometabolic responses of astrocytes
title_full_unstemmed APOE4 drives transcriptional heterogeneity and maladaptive immunometabolic responses of astrocytes
title_short APOE4 drives transcriptional heterogeneity and maladaptive immunometabolic responses of astrocytes
title_sort apoe4 drives transcriptional heterogeneity and maladaptive immunometabolic responses of astrocytes
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9934552/
https://www.ncbi.nlm.nih.gov/pubmed/36798317
http://dx.doi.org/10.1101/2023.02.06.527204
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