current research projects
Short-term estradiol use in middle-age: implications for female cognitive aging. This work is supported by NIH Grant RF1AG041374.
Administration of estrogens begun during a critical window near menopause is hypothesized to prevent or delay age-associated cognitive decline and Alzheimer's disease and related dementias. However, due to potential health risks women often limit use of estrogen therapy to a few years to treat menopausal symptoms. The long-term consequences for the brain, cognitive aging, and risk of dementia of short-term use of estrogens are unknown. The long-term goal of the research is to determine the consequences for the female brain and for female cognitive aging of short-term exposure to estrogens during middle-age such as that used by women during the menopausal transition.
Impact of hypertension and high-fat diet on mechanisms by which estradiol affects the hippocampal memory system. This work is supported by P01AG071746 -Subproject 8453.
Our recently awarded Program Project Grant, Estrogens, Cardiometabolic Health, and Female Cognitive Aging, will determine impacts of cardiometabolic disease on the ability of estrogens to provide benefits to the brain and cognition in an aging female rodent model by testing concurrent multiple hypotheses involving multiple mechanisms that may act independently or interactively. The Daniel lab is overseeing one of four interrelated research projects that is part of the synergistic investigation.
The role of menopausal hormone therapy in the maintenance of cognitive skills as women age is unresolved. Results of basic and preclinical research provide convincing evidence that estrogens exert neuroprotective effects in the brain, including in the hippocampus, a brain area critical for memory and one that is vulnerable to effects of aging. Thus, expectations were that estrogens would benefit the brain and cognitive aging in women including decreasing risk or delaying onset of Alzheimer’s disease and related dementias. However, clinical data have been equivocal as to the benefits of hormone therapy for cognition, with effects ranging from beneficial to harmful. Whereas preclinical research is primarily conducted in models of healthy aging, clinical research often includes subjects with diverse health status. To reconcile this evidence gap, we will determine the impacts of cardiometabolic health and disease on the ability of estrogens to exert protective effects on the hippocampal memory system. Our goal is to establish under which conditions estrogen treatment will or will not provide benefits to the hippocampal-mediated cognitive trajectory, a determination with implications for the prevention or delaying of age-associated memory disorders, including Alzheimer’s disease and related dementias.
Research in our lab using rodent models reveals that midlife estrogen treatment initiated at the time of cessation of ovarian function exerts positive effects on the hippocampus and memory due to its ability to regulate estrogen receptor (ER) α levels. Specifically, midlife estradiol treatment in recently ovariectomized rats results in lasting memory enhancements as well as increases in hippocampal levels of ERα, effects that persist into old age and well beyond the period of estradiol exposure. The importance of ERα to successful cognitive aging is supported by data indicating a causal relationship between increased levels of hippocampal ERα and enhanced memory even in the absence of ovarian estrogens. The mechanisms by which midlife estradiol treatment exert lasting impacts on levels of ERα involve protection of the receptor from degradation via the ubiquitin/proteasome system. Interestingly, when estradiol treatment is delayed and initiated well after ovariectomy-associated weight gain has taken place, estradiol has no impact on memory or ERα levels in the hippocampus, suggesting disruption of the ability of estradiol to protect ERα from degradation in these animals. The central hypothesis to be tested by the currently proposed studies is that in aging females, cardiometabolic disease, due to associated dysfunction of the ubiquitin/proteasome system, disrupts the ability of estrogens to regulate levels of ERα in the hippocampus, regulation that is necessary for midlife estradiol treatment to exert lasting positive impacts on memory during aging.