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

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 immunometab-olism. 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 immunometa-bolic changes across the APOE4 glial transcriptome, specifically in subsets of metabolically distinct micro-glia enriched in the E4 brain during aging or following an inflammatory challenge. E4 microglia display increased Hif1a 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 re-sources for discovery and validation research.

Automated summary

This study investigates the role of APOE in different age, neuroinflammatory, and AD pathological processes by combining bulk, single-cell, and spatial transcriptomics with cell-specific and spatially resolved metabolic analyses. The findings suggest that APOE4 microglia exhibit immunometabolic changes and altered lipid metabolism, potentially contributing to the association with metabolic dysfunction and heightened pro-inflammatory response.