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摘要 基础和临床前研究提供了令人信服的证据，这些证据逃脱了运动神经保护作用 海马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氏病的影响。 那就是期望的是，更年期的马内治疗将是神经保护性的，并降低了 女性的阿尔茨海默氏病和相关痴呆症。但是，马酮治疗在大脑上的好处 认知尚未解决。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潜水员健康状况的受试者。为了解决这一证据差距，我们将 确定心脏代谢状态对雌激素有益于海马的能力的影响 内存系统。我们的中心假设是，在衰老的女性中，由于相关 泛素/蛋白酶体系统的功能障碍，破坏了进化调节ERα水平的能力 海马，雌二醇治疗所必需的调节，以执行对 衰老期间的记忆。该假设将通过以下特定目的检验：1）确定是否个人 海马记忆系统对中年雌二醇治疗的反应差异与 心脏代谢健康的个体差异； 2）确定雌二醇是否对海马的影响 衰老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 雌二醇对衰老女性海马记忆系统的影响受心血管疾病的影响。 第一个目标下的实验将使用纵向研究设计和中年雌二醇的大鼠模型 卵巢功能停止或延迟后立即给予哪种雌二醇 评估体内脂肪积累，葡萄糖调节，心血管功能之间的关系， 海马功能以及从中年到老年的记忆。第二个目标下的实验将暴露 中年雌性大鼠在中年雌二醇治疗倡议之前或之后进行高脂饮食 a）评估中年雌二醇对海马ERα水平的影响的能力， 海马功能和内存； b）确定海马ERα的水平是否差异 在高脂饮食或对照饮食上，在衰老的女性中影响记忆和海马。第三个实验 AIM将使用血管紧张素II依赖性高血压大鼠模型来评估中年雌二醇的能力 对海马ERα的水平，海马功能的度量和记忆力执行影响； b）确定 如果海马ERα水平的增加对衰老女性的记忆和海马的影响有所不同 没有或没有高血压。结果将确定雌激素治疗提供的条件下 对海马介导的认知轨迹的有益影响，这是对 预防或延迟衰老相关的记忆障碍，包括阿尔茨海默氏病及相关的 痴呆症。