APOE modulates microglial immunometabolism in response to age, amyloid pathology, and inflammatory challenge.

Autor:	Lee S; Sanders Brown Center on Aging, University of Kentucky, Lexington, KY 40536, USA., Devanney NA; Department of Physiology, University of Kentucky, Lexington, KY 40536, USA; Sanders Brown Center on Aging, University of Kentucky, Lexington, KY 40536, USA., Golden LR; Department of Physiology, University of Kentucky, Lexington, KY 40536, USA., Smith CT; Department of Physiology, University of Kentucky, Lexington, KY 40536, USA., Schwartz JL; Sanders Brown Center on Aging, University of Kentucky, Lexington, KY 40536, USA., Walsh AE; Department of Physiology, University of Kentucky, Lexington, KY 40536, USA., Clarke HA; Department of Neuroscience, University of Kentucky, Lexington, KY 40536, USA; Department of Biochemistry & Molecular Biology, College of Medicine, University of Florida, Gainesville, FL, USA; Center for Advanced Spatial Biomolecule Research, University of Florida, Gainesville, FL, USA., Goulding DS; Sanders Brown Center on Aging, University of Kentucky, Lexington, KY 40536, USA., Allenger EJ; Department of Physiology, University of Kentucky, Lexington, KY 40536, USA., Morillo-Segovia G; Department of Physiology, University of Kentucky, Lexington, KY 40536, USA., Friday CM; Department of Physiology, University of Kentucky, Lexington, KY 40536, USA., Gorman AA; Sanders Brown Center on Aging, University of Kentucky, Lexington, KY 40536, USA., Hawkinson TR; Department of Neuroscience, University of Kentucky, Lexington, KY 40536, USA; Department of Biochemistry & Molecular Biology, College of Medicine, University of Florida, Gainesville, FL, USA; Center for Advanced Spatial Biomolecule Research, University of Florida, Gainesville, FL, USA., MacLean SM; Department of Physiology, University of Kentucky, Lexington, KY 40536, USA., Williams HC; Department of Physiology, University of Kentucky, Lexington, KY 40536, USA., Sun RC; Sanders Brown Center on Aging, University of Kentucky, Lexington, KY 40536, USA; Department of Neuroscience, University of Kentucky, Lexington, KY 40536, USA; Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA; Department of Biochemistry & Molecular Biology, College of Medicine, University of Florida, Gainesville, FL, USA; Center for Advanced Spatial Biomolecule Research, University of Florida, Gainesville, FL, USA., Morganti JM; Sanders Brown Center on Aging, University of Kentucky, Lexington, KY 40536, USA; Department of Neuroscience, University of Kentucky, Lexington, KY 40536, USA. Electronic address: josh.morganti@uky.edu., Johnson LA; Department of Physiology, University of Kentucky, Lexington, KY 40536, USA; Sanders Brown Center on Aging, University of Kentucky, Lexington, KY 40536, USA. Electronic address: johnson.lance@uky.edu.
Jazyk:	angličtina
Zdroj:	Cell reports [Cell Rep] 2023 Mar 28; Vol. 42 (3), pp. 112196. Date of Electronic Publication: 2023 Mar 03.
DOI:	10.1016/j.celrep.2023.112196
Abstrakt:	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. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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