Abstract
Women are disproportionately affected by Alzheimer’s disease (AD), having nearly twice the incidence as well as worse pathological outcomes than their male counterparts. The mechanisms behind this sexual dimorphism are complex but may involve the hormonal changes that occur later in a woman’s life as she traverses through menopause. This dissertation aims to help better understand sexual dimorphism in the context of AD. First, I explore the sexually dimorphic response to a histone deacetylase (HDAC) inhibitor in the triple-transgenic AD (3xTg-AD) mouse. I find large sex-dependent variations in response to the HDAC inhibitor in immune response and transcriptomic changes. Secondly, I investigate the effects of accelerated ovarian failure (OF) to model menopause in the 3xTg-AD mouse. The ovotoxin, 4-vinylcyclohexene diepoxide, accelerated ovarian follicle loss, resulting in reduced levels of circulating progesterone. Animals that underwent ovarian failure had decreased performance in behavioral tests of learning and memory, consistent with an accelerated AD phenotype. OF accelerated age-related impaired glucose tolerance and caused insulin resistance. Notably, the severity of these peripheral metabolic changes correlated with cognitive impairment. Transcriptomic analyses of the hippocampus identified 19 regulated genes in the OF mice including some previously linked to AD, including inflammation-associated genes C4b, Ifit3b, and Cxcl13 and the GABA receptor Gabrg2. My findings highlight key cognitive, metabolic, and molecular changes driven by accelerated age-related decline in ovarian function. Importantly, this mouse model of menopause provides a valuable tool for identifying drivers of sexual dimorphism in AD.