Impact of hypertension and high-fat diet on mechanisms by which estradiol affects the hippocampal memory system.

高血压和高脂肪饮食对雌二醇影响海马记忆系统机制的影响。

• 批准号: 10579237
• 负责人: JILL M DANIEL
• 金额: $ 46.61万
• 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/10579237
• 关键词: Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Angiotensin II; Animals; Area; Basic Science; Body fat; Body measure procedure; Brain; Cardiometabolic Disease; Cardiovascular Diseases; Cardiovascular Physiology; Clinical Data; Clinical Research; Cognition; Cognitive; Cognitive Therapy; Cognitive aging; Data; Disease; Estradiol; Estrogen Receptor alpha; Estrogen Therapy; Estrogens; Fatty acid glycerol esters; Female; Functional disorder; Goals; Health; Health Status; High Fat Diet; Hippocampus; Hypertension; Impairment; Individual Differences; Longitudinal Studies; Maintenance; Measures; Mediating; Memory; Memory Disorders; Modeling; Obesity; Ovarian; Ovariectomy; Prevention; Rattus; Regulation; Research; Research Design; Risk; Rodent Model; Role; System; Testing; Time; Ubiquitin; Weight Gain; Woman; age effect; blood glucose regulation; cardiometabolism; cognitive skill; dietary control; expectation; experimental study; healthy aging; hormone therapy; human old age (65+); hypertensive; menopausal hormone therapy; middle age; multicatalytic endopeptidase complex; neuroprotection; pre-clinical research; protective effect; receptor; response

Project 1 Summary Basic and pre-clinical research provides convincing evidence that estrogens exert neuroprotective effects in the hippocampus, a brain area critical for memory and vulnerable to effects of aging and Alzheimer’s disease. Thus, expectations were that menopausal hormone therapy would be neuroprotective and decrease the risk of Alzheimer’s disease and related dementias in women. However, the benefits of hormone therapy on the brain and cognition are unresolved. 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 impacts of cardiometabolic status on the ability of estrogens to beneficially impact the hippocampal memory system. Our central hypothesis 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 estradiol treatment to exert lasting positive effects on memory during aging. The hypothesis will be tested by the following specific aims: 1) determine if individual differences in the response to midlife estradiol treatment on the hippocampal memory system are associated with individual differences in cardiometabolic health; 2) determine if estradiol effects on the hippocampal memory system in aging females are impacted by obesity and impaired glucose regulation; and 3) determine if estradiol effects on the hippocampal memory system in aging females are impacted by cardiovascular disease. Experiments under the first aim will use a longitudinal study design and a rat model of midlife estradiol use—in which estradiol is administered either immediately after the cessation of ovarian function or after a delay—to assess relationships between measures of body fat accumulation, glucose regulation, cardiovascular function, hippocampal function, and memory from middle to old age. Experiments under the second aim will expose middle-aged female rats to a high-fat or control diet before or after the initiation of midlife estradiol treatment and a) assess the ability of midlife estradiol to exert effects on levels of hippocampal ERα, measures of hippocampal function, and memory; and b) determine if increasing levels of hippocampal ERα differentially affect memory and the hippocampus in aging females on high-fat or control diets. Experiments under the third aim will use an angiotensin II-dependent hypertensive rat model to a) assess the ability of midlife estradiol to exert effects on levels of hippocampal ERα, measures of hippocampal function, and memory; and b) determine if increasing levels of hippocampal ERα differentially affect memory and the hippocampus in aging females without or without hypertension. Results will determine under which conditions estrogen treatment provides beneficial effects to the hippocampally mediated cognitive trajectory, a determination with implications for the prevention or delaying of aging-associated memory disorders, including Alzheimer’s disease and related dementias.

项目1概要 基础和临床前研究提供了令人信服的证据，证明雌激素对神经保护作用 海马体是一个对记忆至关重要的大脑区域，容易受到衰老和阿尔茨海默病的影响。 因此，人们期望更年期激素疗法能够起到神经保护作用并降低患绝经期激素的风险。 女性阿尔茨海默病和相关痴呆症然而，激素治疗对大脑的好处。 和认知尚未解决，而临床前研究主要是在健康衰老模型中进行的， 临床研究通常包括具有健康状况的受试者，为了弥合这种不同的证据差距，我们将 确定心脏代谢状态对雌激素有益影响海马的能力的影响 我们的中心假设是，在老年女性中，心脏代谢疾病是由于相关的。 泛素/蛋白酶体系统功能障碍，破坏雌激素调节 ERα 水平的能力 海马体的调节是雌二醇治疗发挥持久积极作用所必需的 该假设将通过以下具体目标进行检验：1）确定个体是否存在衰老过程中的记忆。 海马记忆系统对中年雌二醇治疗的反应差异相关 心脏代谢健康存在个体差异；2) 确定雌二醇是否对海马有影响 老年女性的记忆系统受到肥胖和葡萄糖调节受损的影响；3) 确定是否 雌二醇对老年女性海马记忆系统的影响受到心血管疾病的影响。 第一个目标下的实验将使用纵向研究设计和中年雌二醇使用的大鼠模型—— 哪种雌二醇要么在卵巢功能停止后立即施用，要么在延迟后施用—— 评估身体脂肪积累、血糖调节、心血管功能等指标之间的关系， 第二个目标下的实验将揭示海马功能和中老年记忆。 中年雌性大鼠在开始中年雌二醇治疗之前或之后接受高脂肪或控制饮食 a) 评估中年雌二醇对海马 ERα 水平产生影响的能力，测量 海马功能和记忆；b) 确定海马 ERα 水平的增加是否存在差异 第三项实验对高脂肪或对照饮食的老年女性的记忆力和海马体产生影响。 目标将使用血管紧张素 II 依赖性高血压大鼠模型来 a) 评估中年雌二醇的能力 对海马 ERα 水平、海马功能测量和记忆力产生影响；b) 确定 海马 ERα 水平的增加是否会对老年女性的记忆力和海马体产生不同的影响 有或没有高血压的结果将决定雌激素治疗在什么条件下提供。 对海马介导的认知轨迹的有益影响，这一决定对 预防或延缓与衰老相关的记忆障碍，包括阿尔茨海默病和相关疾病 痴呆症。