APOE modulates microglial immunometabolism in response to age, amyloid pathology, and inflammatory challenge
APOE modulates microglial immunometabolism in response to age, amyloid pathology, and inflammatory challenge
Summary 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 to systematically address the role of APOE across age, neuroinflammation, and AD pathology. RNAseq 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, a disrupted TCA cycle, and are inherently pro-glycolytic, while spatial transcriptomics and MALDI 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.
Devanney Nicholas A.、Friday Cassi M.、Morillo-Segovia Gabriella、Hawkinson Tara R.、Lee Sangderk、Walsh Adeline E.、Goulding Danielle S.、Allenger Elizabeth J.、Williams Holden C.、MacLean Steven M.、Smith Cathryn T.、Clarke Harrison A.、Gorman Amy A.、Schwarz James L.、Morganti Josh M.、Johnson Lance A.、Sun Ramon C.、Golden Lesley R.
Department of Physiology, University of Kentucky||Sanders Brown Center on Aging, University of KentuckyDepartment of Physiology, University of KentuckyDepartment of Physiology, University of KentuckyDepartment of Neuroscience, University of KentuckyDepartment of Physiology, University of Kentucky||Sanders Brown Center on Aging, University of KentuckyDepartment of Physiology, University of KentuckySanders Brown Center on Aging, University of KentuckyDepartment of Physiology, University of KentuckyDepartment of Physiology, University of KentuckyDepartment of Physiology, University of KentuckyDepartment of Physiology, University of KentuckyDepartment of Neuroscience, University of KentuckySanders Brown Center on Aging, University of KentuckySanders Brown Center on Aging, University of KentuckySanders Brown Center on Aging, University of Kentucky||Department of Neuroscience, University of KentuckyDepartment of Physiology, University of Kentucky||Sanders Brown Center on Aging, University of KentuckySanders Brown Center on Aging, University of Kentucky||Department of Neuroscience, University of Kentucky||Markey Cancer Center, University of KentuckyDepartment of Physiology, University of Kentucky
基础医学神经病学、精神病学生物科学研究方法、生物科学研究技术
Devanney Nicholas A.,Friday Cassi M.,Morillo-Segovia Gabriella,Hawkinson Tara R.,Lee Sangderk,Walsh Adeline E.,Goulding Danielle S.,Allenger Elizabeth J.,Williams Holden C.,MacLean Steven M.,Smith Cathryn T.,Clarke Harrison A.,Gorman Amy A.,Schwarz James L.,Morganti Josh M.,Johnson Lance A.,Sun Ramon C.,Golden Lesley R..APOE modulates microglial immunometabolism in response to age, amyloid pathology, and inflammatory challenge[EB/OL].(2025-03-28)[2025-06-06].https://www.biorxiv.org/content/10.1101/2022.05.17.492361.点此复制
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