Sex chromosomes and gonads modify microglial-mediated pathology in a mouse model of Alzheimer's disease

Alzheimer's disease (AD) is a neurodegenerative disorder disproportionally affecting women with sex-specific disease manifestations and therapeutic responses. Microglial-mediated inflammation occurs in response to and perpetuates disease processes, and fundamental sex differences in microglia may contribute to these sex biases. Both sex chromosomes and gonad-derived hormones shape immune responses, but their contribution to immune-mediated mechanisms underlying the sex bias in AD is unclear. Crossing the Four Core Genotype (FCG) model to separate sex chromosome and gonad-derived hormone effects to the 5xFAD model, we found the sex chromosome complement impacted microgliosis, neuroinflammation, plaque burden and neuritic dystrophy. Modification of pathology largely correlated with microgliosis, and sex chromosomes and gonad-derived hormones influenced plaque remodeling and microglial CD11c expression. Our results provide potential trajectories for studying and targeting microglial-mediated sex differences and emphasize the complex interplay between sex chromosomes and hormones during AD.