As we get older, our mental functions get less flexible and our memory declines. While our mind can adapt to simple lapses in function, memory loss is generally progressive and can eventually interfere with daily life. Alzheimer’s disease is the most common cause of dementia, which involves the abnormal buildup of misfolded protein “plaques” in the brain. Despite significant research efforts aimed at Alzheimer’s therapies, there are currently no cures and very few treatment options. There is an urgent need for creative approaches to identify new targets for therapeutic intervention.

Microglia, the brain’s resident macrophages, have emerged as a key cell type in Alzheimer’s disease. Male and female microglia display divergent responses to AD, which include distinct morphology, phagocytic capacity, cell surface marker expression, and response to inflammatory stimuli. Microgliosis is a pathological hallmark of AD characterized by microglia diversification into a variety of phenotypic states (both protective and destructive). We hypothesize that sex-chromosomally and hormonally driven processes contribute mechanistically to the sex differential microglial response to AD. Our goal is to identify novel pathways that confer risk or resilience for AD to inform therapeutic development.

In addition to determining sex, sex chromosomes play important roles in programming sex-specific features across body systems. Due to the sex chromosome imbalance between males (XY) and females (XX), epigenetic dosage compensation mechanisms, such as X-chromosome inactivation, have evolved. Sex chromosomal mechanisms, such as X-chromosome inactivation and mosaic loss-of-Y have been implicated in AD. We will use multi-omic single-cell techniques coupled with disease models to identify how sex chromosomes impact AD progression.

In terms of sex hormones, we are interested in how estrogen signaling through microglia may contribute to the sex differences seen in neuroinflammation with aging and AD. We will use menopausal models, transgenic deletion of estrogen receptors, and estrogen replacement therapies to test the effect of estrogen signaling modulation on microglial phenotypic responses to aging and disease.