Estrogen, Astrocyte Reactivity, and Sex Differences in Alzheimer's Disease

To ascertain the mechanisms connecting estrogen loss in the brain to sex difference in AD vulnerability, we propose the following aims: 1. Determine whether aromatase deletion and estradiol deficiency drive sex-specific differences in astrocyte reactivity, neurodegeneration, and memory loss. We will use transgenic and systemic approaches to restore brain aromatase expression or estrogen action in bArKO and tArKO mice as phenotype rescue strategies. The estrogen/ERα-mediated genomic mechanisms responsible for the suppression of sex-specific hippocampal astrocyte reactivity, neurodegeneration, and memory loss will be determined using integrative genome-wide analyses employing RNA-seq, ERα-ChIP-seq, and ATAC-seq on primary hippocampal astrocytes. 2. Determine whether conditional knockout of ERα in astrocytes in a mouse model of AD (APPNL-G-F) accelerates astrocyte reactivity, memory loss, and AD-related neuropathology. In parallel, we will assess tissue estrogen levels, expression of aromatase and ERα, and sex-specific expression of reactive astrocyte-related genes and their correlation with the severity of AD pathology in postmortem hippocampal tissues and memory deficits in medical records of women and age-matched men with AD. We expect that the findings from the proposed studies will identify new drug targets and lead to novel intervention strategies for the prevention and treatment of AD