Estrogens, Cardiometabolic Health, and Female Cognitive Aging

雌激素、心脏代谢健康和女性认知衰老

• 批准号: 10334228
• 负责人: JILL M DANIEL
• 金额: $ 282.27万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10334228
• 关键词: Affect; Aging; Alzheimer' s Disease; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Attenuated; Behavior; Blood Vessels; Brain; Cardiometabolic Disease; Cardiovascular Diseases; Cardiovascular system; Clinical Data; Cognition; Cognition Disorders; Cognitive; Cognitive aging; Cyclophosphamide; Development; Diet; Disease; Ensure; Estradiol; Estrogen Receptor alpha; Estrogen Receptors; Estrogen Therapy; Estrogens; Female; Functional disorder; Goals; Health; Health Status; High Fat Diet; Hippocampus (Brain); Hormones; Hypertension; Impaired cognition; Impairment; Incidence; Insulin Resistance; Investigation; Leadership; Long-Term Potentiation; Measurement; Memory; Menopause; Metabolic; Metabolic syndrome; Modeling; Molecular; NOS3 gene; Nerve Degeneration; Non-Insulin-Dependent Diabetes Mellitus; Ovarian; Physiological; Pre-Clinical Model; Procedures; Process; Program Research Project Grants; Recommendation; Regulation; Reproducibility of Results; Research; Risk Factors; Rodent Model; Signal Pathway; Synaptic plasticity; System; Testing; Ubiquitin; Variant; Vascular Dementia; Weight Gain; Woman; age related; aging brain; blood glucose regulation; cardiometabolism; cognitive change; cognitive function; design; experimental study; hormone therapy; middle age; multicatalytic endopeptidase complex; neurovascular coupling; personalized approach; preservation; programs; response

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.

总体总结 更年期卵巢功能丧失被重新认为是阿尔茨海默病及相关疾病的危险因素 临床前模型研究表明，雌激素具有神经保护作用，可以积极促进痴呆症的发生。 然而，临床数据对于其益处尚不明确。 更年期雌激素治疗对大脑和认知的影响女性雌激素治疗的反应。 表明高血压和代谢综合征等已有疾病可以调节机制 这些改变可能会导致雌激素提供的保护作用减弱或逆转。 预防认知能力下降、阿尔茨海默病和相关痴呆症。 心脏代谢状态对外源性雌激素对大脑有益的能力的影响 和认知在老年雌性啮齿动物模型中的总体假设是雌激素的施用。 如果在健康受试者中开始，老年女性将有益于大脑和认知，但如果在以下情况下则不会带来任何好处： 在存在心脏代谢疾病的情况下引发这些不同的影响的机制是。 涉及雌激素直接作用于大脑记忆的机制的改变 雌激素作用于心脏代谢系统的系统和机制，进而影响大脑 四个项目下的实验将检验这一假设。 假设心脏代谢疾病是由于泛素/蛋白酶体系统的相关功能障碍引起的， 会破坏雌激素调节海马 ERα 水平的能力，这种调节是必要的 项目 2 将检验中年雌二醇治疗对记忆力产生持久影响的假设。 心脏代谢疾病的存在会削弱神经血管，从而阻碍雌激素的有益认知作用 通过内皮一氧化氮合酶解偶联进行偶联，从而损害局部网络活动和突触 保护功能性皮层回路所需的可塑性，因此项目 3 将测试认知功能。 假设心血管疾病改变雌激素受体谱，改变下游分子 信号通路并减弱其保护性血管作用以及随后对认知的影响。 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 雌二醇对葡萄糖稳态中枢调节的有益影响是必要的，海马长 术语增强和海马体依赖性认知功能将提供。 领导该计划并确保所有计划组成部分的整合。 激素和行为核心将提供模型和程序的关键一致性，以确保科学性 跨项目结果的严谨性和可重复性 结果将确定雌激素发挥作用的条件。 治疗将（或不会）改变认知衰老轨迹，从而可能减少或延迟年龄 相关的认知疾病，包括阿尔茨海默病和血管性痴呆。