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

项目1摘要 基础和临床前研究提供了令人信服的证据，表明雌激素在 海马体，这是大脑中对记忆至关重要的区域，容易受到衰老和阿尔茨海默病的影响。 因此，人们的预期是，更年期激素治疗将具有神经保护作用，并降低 妇女中的阿尔茨海默病和相关痴呆。然而，荷尔蒙疗法对大脑的好处 和认知都是未解决的。而临床前研究主要是在健康衰老的模型中进行的， 临床研究通常包括不同健康状况的受试者。为了调和这一证据差距，我们将 确定心脏代谢状态对雌激素有益影响海马区能力的影响 存储系统。我们的中心假设是，在老年女性中，心脏代谢性疾病与 泛素/蛋白酶体系统功能障碍，扰乱雌激素调节ERα水平的能力 海马体，雌激素治疗发挥持久积极作用所必需的调节 衰老过程中的记忆。这一假设将通过以下具体目标进行检验：1)确定个人 中年雌激素治疗对海马区记忆系统的反应存在差异 心脏代谢健康的个体差异；2)确定雌二醇是否对海马区有影响 老年女性的记忆系统受到肥胖和糖调节受损的影响；以及3)确定 雌激素对老年女性海马体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采用纵向研究设计和中年雌激素使用的大鼠模型。 哪种雌二醇在卵巢功能停止后立即给药或在延迟后给药- 评估身体脂肪堆积、血糖调节、心血管功能、 海马体功能，中老年记忆。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前后给予高脂饮食或对照饮食 以及a)评估中年雌二醇对海马区ERα水平的影响能力，测量 海马区功能和记忆；以及b)确定海马区ERα水平的升高是否存在差异 影响高脂肪饮食或对照饮食的老年女性的记忆和海马体。第三章下的实验 AIM将使用血管紧张素II依赖的高血压大鼠模型来a)评估中年雌二醇对 对海马区ERα水平、海马区功能测量和记忆产生影响；以及b)确定 如果海马区ERα水平升高对老年女性的记忆和海马区产生不同的影响 无论有没有高血压。结果将决定雌激素治疗在哪些条件下提供 对海马体介导的认知轨迹的有益影响，这一确定对 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 痴呆症。

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.