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Abstract

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.

Document Type

Article

Publication Date

2026

Notes/Citation Information

© The Author(s) 2026. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creati vecommons.org/licenses/by-nc-nd/4.0/

Digital Object Identifier (DOI)

https://doi.org/10.1186/s12974-026-03698-2

Funding Information

This project was supported by the National Institute on Aging, National Institute of Neurological Disorders and Stroke at the National Institutes of Health, BrightFocus Foundation, and Alzheimer’s Association through Grants R01AG068330 (SLM), BrightFocus Foundation (A20201775S; SLM), RF1AG059717 (SE) and R21AG068370 (SE), K01 AG062683 (JTCW), R56 AG078733 (JTCW), Bright Focus Foundation (JTCW), R01AG060056 (LAJ), R01AG062550 (LAJ), R01AG080589 (LAJ), Cure Alzheimer’s Fund (LAJ and JMM), Alzheimer’s Association (LAJ and JMM), R01AG070830 (JMM), and RF1NS118558 (JMM). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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