Towriss, M. | bioRxiv Science

bioRxiv2026

Sex and APOE Genotype Differentially Shape Microglial Transcriptomic Profiles Across the Hippocampus and Cortex

Female sex and the APOEe4 allele are top risk factors for Alzheimers disease (AD). Microglia play a role in the pathogenesis of AD, yet how sex and APOE genotype affect microglia remain poorly understood. Here, we characterized the transcriptomic and morphological profiles in the hippocampus and cortex of microglia from humanized APOEe3 and APOEe4 mice of males and females. The hAPOEe4 genotype was associated with sex-dependent effects on microglia co-expression modules in both brain regions, involving cellular stress and immunometabolism processes. In females, a hippocampal cell cycle module was supported by reduced microglial proliferation. Cortical modules were enriched for lipid metabolism and immune-related processes whose expression decreased in females but increased in male hAPOEe4. Male, but not female, hAPOEe4 microglia shifted toward an ameboid state in both regions. Together, these findings reveal sex-dependent microglial responses to APOEe4 across brain regions and highlight the need to incorporate sex-specific approaches into AD research.

neuroscience↗

bioRxiv2026

Microbiome-derived Short Chain Fatty Acids modulate microglial inflammatory responses in a sex- and metabolite-specific manner

Microbes residing in the gastrointestinal tract exert immunomodulatory impacts on the brain through the gut-brain axis. Short-chain fatty acids (SCFAs) produced by bacterial fermentation of dietary fiber can enter the brain parenchyma and are implicated in microglia-mediated inflammation. While the gut microbiome is required to maintain microglial homeostasis, the mechanisms by which microbiota-derived metabolites affect microglia remains unknown. We examined the roles of SCFAs, specifically butyrate, propionate and acetate, on microglial function in response to SCFAs both in vitro using BV2 cells and in vivo in mice. We observed in vivo that SCFAs impact microglial transcriptional responses to LPS in a sex- and metabolite-specific manner with butyrate having the strongest effect. Enriched gene sets included signatures associated with LPS-responsive microglia, Arg1-positive microglia, microglial cell cycle related genes and genes affiliated with changes in microglial morphology. We observed a similar effect in vitro, where metabolite administration enhanced phagocytosis, blunted proliferation and nitric oxide production. We then evaluated global histone modification levels following metabolite treatment and detected an enhancement of H3K9ac, H3K27ac, and H3K4me3 both in vivo and in BV2 cells treated with butyrate. Finally, we showed that butyrate is a potent HDAC inhibitor possibly contributing to enhanced acetylation. Hence, our findings suggest that SCFAs impact microglial function in a metabolite- and sex-specific manner, and that butyrate blunts inflammation by regulating microglial histone acetylation. Our results provide a more in-depth understanding of gut microbiome-microglia crosstalk, opening the door for new microbiome- and microglia-targeted therapies. HighlightsXxxx

neuroscience↗