Targeting NMDA Receptors and Brain Estradiol to Rescue Memory in Aging Females

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PROJECT SUMMARY/ABSTRACT Aging women are disproportionately affected by severe memory loss and Alzheimer's disease (AD). The precise mechanisms that impair memory in older women are not fully understood, but the transition into menopause at middle-age, and the ensuing decrease in circulating estrogens, is a consequential inflection point of the female lifespan. Numerous studies document an association between the loss of ovarian hormones, especially estradiol (E2), at menopause and the loss of their protective effects on neural health and cognition. Under normal circumstances, E2 acts upon NMDA receptors (NMDARs) that are essential for learning and memory. In the context of brain disorders, NMDARs gate excitotoxic signaling that can exacerbate neurodegeneration. Loss of E2 in the brain is plausibly situated to influence shifts in NMDAR contributions to neuronal signaling versus survival in brain aging and moderate the effects of AD therapeutics. Consequently, there is a pressing need to develop targeted therapeutics to precisely restore brain E2 and NMDAR activity that could reverse memory loss and reduce AD risk in older, post-menopausal women. Consistent with this view, our preliminary data reveal that a novel therapeutic that potentiates NMDAR function reverses memory loss in older male rats but not in age- matched female rats. The goal of this project is to determine the mechanisms by which female sex and E2 loss accelerate age-related decline of memory and NMDAR functions and to rejuvenate brain E2 levels and sensitivity to NMDAR-directed drugs to rescue memory in older, hormone-deficient females. This project will use normally aging rats to 1) compare effects of approved and novel NMDAR therapeutics on brain and behavior of aging male and female rats and 2) investigate the effects of whole body and brain-specific replacement of E2 in surgically estrogen-deficient, aging females. These studies of NMDAR-directed compounds in well-controlled animal models of aging and estrogen deficiency will be significant because they can provide the necessary mechanistic insights to guide the translation and development of new, targeted therapeutics to prescribe to peri- and post-menopausal women at risk for age-related memory disorders. More broadly, identifying sex-specific and age-appropriate strategies to decelerate fundamental mechanisms that drive neuronal and cognitive aging will broadly improve health outcomes for older women who comprise the largest fraction of those at-risk for AD. These objectives are within the scientific scope of the University of South Carolina's COBRE on Targeted Therapeutics, contribute a unique and distinct complement to ongoing studies of NMDAR-directed therapeutics, and will accomplish rigorous scientific research on differential rates of cognitive aging and the underlying mechanisms of aging leading to increased risk of Alzheimer's disease in pre- and post-menopausal women, specific areas of interest for the National Institute on Aging related to Women's Health.