current research projects
Short-term estradiol use in middle-age: implications for female cognitive aging. This work is supported by NIH Grant R01AG041374.
Loss of ovarian hormones during menopause coincides with cognitive decline and increased risk of Alzheimer's disease and related dementias. Due to putative health risks associated with prolonged exposure to estrogens, current guidelines recommend limiting hormone therapy to a few years to treat menopausal symptoms. Work from our lab in rodent models of menopause has demonstrated long-lasting benefits of short- term midlife estradiol treatment on hippocampal function and memory through sustained activation of estrogen receptor (ER) α that are likely permanent, persisting long after the estradiol treatment is terminated. These findings correspond with evidence across multiple species, including humans, that elevated levels of brain ERα are associated with enhanced cognitive aging even in the absence of circulating estrogens. Mechanisms by which increased levels of brain ERα enhance cognitive aging in females with a history of previous midlife estradiol treatment is the broad focus of the current research.
The overall hypothesis to be tested by the current studies is that a short-term period of midlife estradiol treatment reverses the negative impact of long- term hormone deprivation on hippocampal function by sustaining levels of brain-derived or neuroestrogens well beyond the period of estradiol treatment. Sustained levels of neuroestrogens allows for insulin-like growth factor-1 (IGF-1) mediated activation of the ERK/MAPK signaling pathway to predominate over the PI3K/Akt pathway, which in turns allows for sustained, continued activation of ERα and subsequent regulation of ERα- mediated genes and proteins important for memory.
Guided by supporting data, this hypothesis is being tested by three aims. In Aim 1, we will use a transgenic mouse model that allows for Cre-dependent site-specific inactivation of ERK signaling to determine its role in the ability of IGF-1 to activate ERα and ERα-regulated genes and proteins and impact memory. In Aim 2, we will use transgenic mouse models and viral vector delivery of ERα to manipulate ERK and ERα signaling to determine the respective roles of ERK and ERα in the ability of midlife estradiol exposure to impact hippocampal neuroestrogen synthesis long-term. In Aim 3, we will use pharmacological manipulations to determine if the detrimental effects of long-term ovarian hormone deprivation on the hippocampus and cognition can be reversed by altering the balance of IGF-1 mediated signaling from PI3K/Akt to ERK/MAPK. Completion of the proposed aims is expected to have a positive impact on the study of cognitive aging by elucidating mechanisms by which the postmenopausal cognitive aging trajectory can be enhanced, results that have implications for preventing or delaying onset of Alzheimer's disease and related dementias.
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.