Microglial interferon signaling and Aβ plaque pathology are enhanced in female 5xFAD Alzheimer’s disease mice, independent of estrous cycle stage

ABSTRACT: Alzheimer’s disease (AD) presents with a sex bias where women are at higher risk and exhibit worse cognitive decline and brain atrophy compared to men. Microglia play a significant role in the pathogenesis and progression of AD and have been shown to be sexually differentiated in health and disease. Whether and how microglia contribute to the sex differences in AD remains to be elucidated. Herein, we characterize the sex differences in microglial transcriptomic changes that occur in females and males in response to amyloid-beta (Aβ). In females, we focus on two hormonally distinct stages of the rodent estrous cycle: proestrus and diestrus. Our transcriptomic data revealed that female microglia are not overtly different at the proestrus or diestrus stages. However, we found stark sex differences between female and male microglia transcriptomes in the 5xFAD brains, where female 5xFAD microglia upregulated genes involved in glycolytic metabolism, antigen presentation, disease-associated microglia, and microglia neurodegenerative phenotype (DAM/MGnD) compared to male 5xFAD microglia. Interestingly, a significant proportion of differentially expressed genes (DEGs) between female and male 5xFAD microglia were interferon-stimulated genes (ISGs), all of which were upregulated in females.

ORGANISM(S): Mus musculus

PROVIDER: GSE306854 | GEO | 2026/01/08

REPOSITORIES: GEO