MON-164 - Hippocampal Dysfunction Associated with Endocrine Transitions in A Preclinical Model of Alzheimer'S Disease

Over 7 million people ages 65 and older within the U.S. are believed to have Alzheimer’s Disease (AD), with nearly two-thirds of these individuals being women. Despite this stark sexual dimorphism in AD prevalence, mechanistic investigations into this heightened risk are lacking. Clinical evidence indicates women who transition to menopause exhibit distinct endophenotypes from age-matched men, including greater amyloid beta (Aβ) deposition and gray and white matter loss, suggesting endocrine changes related to perimenopause may underlie these sex differences. The hippocampus, a primary site of AD pathology, exhibits pockets of hyperexcitability in individuals with AD, largely due to excitatory/inhibitory tone imbalances resulting from GABAergic interneuron loss. Interestingly, novel preclinical data demonstrate hippocampal hyperexcitability in a rodent model of perimenopause. Thus, we posit that the hippocampus is a unique convergence point whereby irregular hormone fluctuations during perimenopause and eventual estrogen depletion lead to aberrant hippocampal function, potentiating the risk of AD in women. Here, we use the 4-vinylcyclohexene diepoxide (VCD) paradigm, a rodent model that produces hormonal fluctuations and ovarian failure consistent with those seen in perimenopause, in transgenic rats expressing mutations in human amyloid precursor protein and presenilin 1 genes, which recapitulate pathological and behavioral phenotypes of AD. To examine longitudinal changes in hippocampal function, animals undergo monthly repetition of hippocampal-dependent behavioral tasks throughout the VCD timeline. Additionally, in vivo electrophysiological recordings of the dorsal hippocampus are performed monthly to measure changes in oscillatory activity in awake, freely moving rats. Consistent with our hypothesis, preliminary results suggest there is an interaction between VCD treatment and AD genotype, whereby VCD-treated TgAD animals display earlier and worsened behavioral phenotypes relative to either the AD genotype or VCD treatment alone. Further, similar trends observed among alterations in hippocampal activity are supported by current electrophysiological data. As this study is ongoing, data presented are still preliminary; however, this study explores the relationship between endocrine aging during the perimenopausal transition and the pathogenesis of AD, which is essential in understanding female-specific risk.

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