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

作者：Sangderk Lee, Nicholas A. Devanney, Lesley R. Golden, Cathryn T Smith, James L. Schwarz, Adeline E. Walsh, Harrison A. Clarke, Danielle S. Goulding, Elizabeth J. Allenger, Gabriella Morillo-Segovia, Cassi Friday, Amy A. Gorman, Tara R. Hawkinson, Steven M. MacLean, Holden C. Williams, Ramon C. Sun, Josh M. Morganti, Lance A. Johnson · 发表于：bioRxiv (Cold Spring Harbor Laboratory) · 年份：2022 · DOI：10.1101/2022.05.17.492361 · 被引用次数：5 · 研究领域：Neuroinflammation and Neurodegeneration Mechanisms、Atherosclerosis and Cardiovascular Diseases、Immune cells in cancer

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.