Loss of ovarian function at menopause is hypothesized to be a risk factor for Alzheimer’s disease and related dementias. Research in preclinical models indicates that estrogens are neuroprotective and can positively impact the cognitive aging trajectory. However, clinical data have been equivocal as to the benefits of menopausal estrogen therapy to the brain and cognition. Variation in response to estrogen therapy in women suggests that pre-existing disease such as hypertension and metabolic syndrome can modulate mechanisms of estrogen action. These alterations may consequently reduce or reverse protections estrogens provide against cognitive decline, Alzheimer’s disease, and related dementias. The Program objective is to determine the impact of cardiometabolic status on the ability of exogenously administered estrogens to benefit the brain and cognition in an aging female rodent model. The overall hypothesis is that administration of estrogens in aging females will benefit the brain and cognition if initiated in healthy subjects, but will provide no benefits if initiated in the presence of cardiometabolic disease. Mechanisms by which these divergent effects occur are hypothesized to involve both alterations in mechanisms by which estrogens act directly on brain memory systems and mechanisms by which estrogens act on cardiometabolic systems, which in turn impact brain memory systems. Experiments under the four Projects will test this hypothesis. Project 1 will test the hypothesis that cardiometabolic disease, due to associated dysfunction of the ubiquitin/proteasome system, will disrupt the ability of estrogens to regulate levels of ERα in the hippocampus, regulation that is necessary for midlife estradiol treatment to exert lasting impacts on memory. Project 2 will test the hypothesis that the presence of cardiometabolic disease impedes estrogen’s beneficial cognitive effects by blunting neurovascular coupling via endothelial nitric oxide synthase uncoupling, thus impairing the local network activity and synaptic plasticity required to preserve functional cortical circuits and therefore for cognition. Project 3 will test the hypothesis that cardiovascular disease alters the estrogen receptor profile, altering downstream molecular signaling pathways and attenuating its protective vascular effects and subsequent impact on cognition. Project 4 will test the hypothesis that insulin resistance caused by high fat diet impairs downstream signaling pathways necessary for estradiol’s beneficial influence on central regulation of glucose homeostasis, hippocampal long- term potentiation, and hippocampus-dependent cognitive function. The Administrative Core will provide leadership to the Program and ensure integration of all Program components. The Cardiometabolic and Hormones and Behavior Cores will provide critical consistencies in models and procedures to ensure scientific rigor and reproducibility of results across projects. Results will identify conditions under which estrogen treatment will (or will not) change the cognitive aging trajectory that could potentially reduce or delay age- related cognitive disease including Alzheimer’s disease and vascular dementia.
