APOE modulates microglial immunometabolism in response to age, amyloid pathology, and inflammatory challenge
Sangderk Lee,
Nicholas A. Devanney,
Lesley R. Golden,
Cathryn T. Smith,
James L. Schwartz,
Adeline E. Walsh,
Harrison A. Clarke,
Danielle S. Goulding,
Elizabeth J. Allenger,
Gabriella Morillo-Segovia,
Cassi M. Friday,
Amy A. Gorman,
Tara R. Hawkinson,
Steven M. MacLean,
Holden C. Williams,
Ramon C. Sun,
Josh M. Morganti,
Lance A. Johnson
Affiliations
Sangderk Lee
Sanders Brown Center on Aging, University of Kentucky, Lexington, KY 40536, USA
Nicholas A. Devanney
Department of Physiology, University of Kentucky, Lexington, KY 40536, USA; Sanders Brown Center on Aging, University of Kentucky, Lexington, KY 40536, USA
Lesley R. Golden
Department of Physiology, University of Kentucky, Lexington, KY 40536, USA
Cathryn T. Smith
Department of Physiology, University of Kentucky, Lexington, KY 40536, USA
James L. Schwartz
Sanders Brown Center on Aging, University of Kentucky, Lexington, KY 40536, USA
Adeline E. Walsh
Department of Physiology, University of Kentucky, Lexington, KY 40536, USA
Harrison A. Clarke
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
Danielle S. Goulding
Sanders Brown Center on Aging, University of Kentucky, Lexington, KY 40536, USA
Elizabeth J. Allenger
Department of Physiology, University of Kentucky, Lexington, KY 40536, USA
Gabriella Morillo-Segovia
Department of Physiology, University of Kentucky, Lexington, KY 40536, USA
Cassi M. Friday
Department of Physiology, University of Kentucky, Lexington, KY 40536, USA
Amy A. Gorman
Sanders Brown Center on Aging, University of Kentucky, Lexington, KY 40536, USA
Tara R. Hawkinson
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
Steven M. MacLean
Department of Physiology, University of Kentucky, Lexington, KY 40536, USA
Holden C. Williams
Department of Physiology, University of Kentucky, Lexington, KY 40536, USA
Ramon C. Sun
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
Josh M. Morganti
Sanders Brown Center on Aging, University of Kentucky, Lexington, KY 40536, USA; Department of Neuroscience, University of Kentucky, Lexington, KY 40536, USA; Corresponding author
Lance A. Johnson
Department of Physiology, University of Kentucky, Lexington, KY 40536, USA; Sanders Brown Center on Aging, University of Kentucky, Lexington, KY 40536, USA; Corresponding author
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 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.
