Estrogens, Cardiometabolic Health, and Female Cognitive Aging

总体汇总 绝经期卵巢功能丧失被认为是阿尔茨海默病及相关疾病的危险因素。 痴呆症临床前模型研究表明，雌激素具有神经保护作用， 影响认知老化的轨迹。然而，临床数据对以下益处不明确： 更年期雌激素治疗对大脑和认知的影响。女性对雌激素治疗反应的变化 表明，预先存在的疾病，如高血压和代谢综合征，可以调节机制， 雌激素的作用。这些改变可能因此减少或逆转保护雌激素提供 对抗认知能力下降、阿尔茨海默病和相关痴呆症。该计划的目标是确定 心脏代谢状态对外源性雌激素对大脑有益能力的影响 和认知能力的研究。总的假设是， 如果在健康受试者中开始，老年女性将有益于大脑和认知，但如果 在存在心脏代谢疾病的情况下启动。这些不同效应发生的机制是 假设涉及雌激素直接作用于大脑记忆机制的两种改变 雌激素作用于心脏代谢系统的系统和机制，进而影响大脑 记忆系统四个项目下的实验将检验这一假设。项目1将测试 假设由于泛素/蛋白酶体系统相关功能障碍， 将破坏雌激素调节海马体中ERα水平的能力， 中年雌二醇治疗对记忆力产生持久影响。项目2将测试假设， 心脏代谢疾病的存在通过钝化神经血管阻碍了雌激素的有益认知作用 通过内皮型一氧化氮合酶解偶联，从而损害局部网络活性和突触 可塑性是保持功能性皮层回路和认知所必需的。项目3将测试 假设心血管疾病改变了雌激素受体分布，改变了下游分子 信号通路和减弱其保护血管的作用和随后对认知的影响。项目 4将检验由高脂肪饮食引起的胰岛素抵抗损害下游信号通路的假设 雌二醇对葡萄糖稳态的中枢调节的有益影响是必要的，海马长- 术语增强，以及依赖于校园的认知功能。行政核心将提供 领导该计划，并确保所有计划组成部分的整合。心脏代谢和 激素和行为核心将提供关键的模型和程序，以确保科学的 项目间结果的严谨性和可重复性。结果将确定雌激素 治疗将（或不会）改变认知老化轨迹，可能会减少或延迟年龄- 相关的认知疾病，包括阿尔茨海默病和血管性痴呆。

Overall Summary 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.