Estrogen regulation of cholesterol metabolism during myelin damage and repair

Project Summary Women experience neurological diseases like multiple sclerosis and Alzheimer’s disease at a higher prevalence than men, and disease symptoms increase in severity after menopause. These connections suggest that there is a fundamental link between estrogen regulation and brain health. Myelin damage is a feature common to both neurological disease states, however, there are no FDA-approved therapies that directly target myelin repair. The long-term goal of this project is to define how CNS lipids are regulated by estrogen and how this affects neurological disease. The overall objective in this application is to determine how estrogen regulates myelin and myelin lipid components during demyelination and remyelination. Preliminary data presented in the application reveals that cholesterol ester metabolism has dynamic changes in response to myelin damage. Work from other groups demonstrated that estrogen can regulate genes related to cholesterol metabolism during demyelination and remyelination. These data form the basis for the central hypothesis that estrogen signaling maintains myelin and promotes remyelination in part through regulation of cholesterol synthesis and recycling. The central hypothesis will be evaluated by two specific aims: (1) Define how estrogen signaling modulates myelin repair; (2) Map how estrogen signaling affects CNS cholesterol metabolites during myelin damage and repair. The proposed research is innovative, in the applicant’s opinion, because it tackles significant questions in women’s health at the intersection of hormone regulation and neurological disease using an interdisciplinary approach. The proposal also features a novel mouse model of myelin repair developed by the applicant that enables the proposed experiments, which would not be possible with other animal models. Completion of the proposed research will reveal mechanistic insights into how estrogen regulates cholesterol metabolism during CNS demyelination and remyelination. This contribution is expected to be significant because it will reveal how estrogen controls CNS cholesterol during neurological disease and may provide insight into why women experience cognitive decline during menopause and more severe neurological symptoms in CNS diseases after menopause. This will advance this area of women’s health research by providing insights that may lead to the development of pro-remyelination agents that would have clinical benefit in CNS diseases with myelin damage.