Estrogens, Cardiometabolic Health, and Female Cognitive Aging

总体摘要 更年期卵巢功能丧失被认为是阿尔茨海默病及其相关疾病的危险因素 痴呆症。对临床前模型的研究表明，雌激素具有神经保护作用，并且可以 影响认知老化的轨迹。然而，临床数据对此的益处一直模棱两可。 更年期雌激素疗法对大脑和认知的影响。女性对雌激素治疗的反应变化 提示先前存在的疾病，如高血压和代谢综合征，可以调节机制 雌激素的作用。因此，这些改变可能会减少或逆转雌激素提供的保护 对抗认知衰退、阿尔茨海默病和相关的痴呆症。该计划的目标是确定 心脏代谢状态对外源性雌激素造脑能力的影响 以及老年雌性啮齿动物模型中的认知。总体假设是雌激素在体内的应用 如果健康受试者开始衰老，老年女性将有益于大脑和认知，但如果 在存在心脏代谢性疾病的情况下启动。这些不同效应产生的机制是 假设涉及雌激素直接作用于大脑记忆的两种机制的改变 雌激素作用于心脏代谢系统，进而影响大脑的系统和机制 记忆系统。这四个项目下的实验将验证这一假设。项目1将测试 假设心脏代谢性疾病，由于相关的泛素/蛋白酶体系统功能障碍， 会破坏雌激素调节海马区ERα水平的能力，这是必要的调节 中年雌激素治疗对记忆产生持久影响。项目2将测试假设 心脏代谢性疾病的存在通过钝化神经血管来阻碍雌激素的有益认知效应 通过内皮型一氧化氮合酶解偶联，从而损害局部网络活动和突触 可塑性是维持大脑功能环路所必需的，因此也是认知所必需的。项目3将测试 心血管疾病改变雌激素受体特征，改变下游分子的假说 信号通路和减弱其保护血管效应和随后对认知的影响。项目 4将检验高脂肪饮食引起的胰岛素抵抗损害下游信号通路的假设。 雌激素对中枢调节葡萄糖动态平衡的有益影响是必需的，海马长... 术语增强和海马体依赖的认知功能。行政核心将提供 对项目进行领导，确保项目所有组成部分的整合。心脏新陈代谢和 荷尔蒙和行为核心将提供模型和程序的关键一致性，以确保科学 跨项目结果的严格性和可重复性。结果将确定雌激素在什么情况下 治疗将(或不会)改变认知老化的轨迹，这可能会减少或延缓年龄- 与认知相关的疾病，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.