RT Journal Article
SR Electronic
T1 <em>APOE</em> modulates microglial immunometabolism in response to age, amyloid pathology, and inflammatory challenge
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.05.17.492361
DO 10.1101/2022.05.17.492361
A1 Sangderk Lee
A1 Nicholas A. Devanney
A1 Lesley R. Golden
A1 Cathryn T. Smith
A1 James L. Schwarz
A1 Adeline E. Walsh
A1 Harrison A. Clarke
A1 Danielle S. Goulding
A1 Elizabeth J. Allenger
A1 Gabriella Morillo-Segovia
A1 Cassi M. Friday
A1 Amy A. Gorman
A1 Tara R. Hawkinson
A1 Steven M. MacLean
A1 Holden C. Williams
A1 Ramon C. Sun
A1 Josh M. Morganti
A1 Lance A. Johnson
YR 2022
UL http://biorxiv.org/content/early/2022/05/20/2022.05.17.492361.abstract
AB 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.Competing Interest StatementThe authors have declared no competing interest.