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，雌激素发挥神经保护作用， 海马体是大脑中对记忆至关重要的区域，易受衰老和阿尔茨海默病的影响。 因此，人们期望绝经期激素治疗具有神经保护作用， 老年痴呆症和相关痴呆症的妇女。然而，激素治疗对大脑的好处 和认知都没有得到解决。鉴于临床前研究主要是在健康老龄化模型中进行的， 临床研究通常包括具有不同健康状况的受试者。为了弥补这一证据缺口，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 记忆系统我们的中心假设是，在老年女性中，心脏代谢疾病，由于相关的 泛素/蛋白酶体系统的功能障碍，破坏雌激素调节雌激素受体α水平的能力， 海马，调节是必要的雌二醇治疗发挥持久的积极影响， 记忆在老化。该假设将通过以下具体目标进行检验：1）确定个体是否 海马记忆系统对中年雌二醇治疗反应的差异与 心脏代谢健康的个体差异; 2）确定雌二醇是否影响海马 老年女性的记忆系统受到肥胖和葡萄糖调节受损的影响;以及3）确定 雌二醇对老年女性海马记忆系统的作用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二醇使用的大鼠模型， 其中雌二醇在卵巢功能停止后立即施用或在延迟至 评估身体脂肪积累，葡萄糖调节，心血管功能， 海马功能和中老年记忆。第二个目标下的实验将揭示 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对照饮食 和a）评估中年雌二醇对海马ERα水平发挥作用的能力， 海马功能和记忆;和B）确定海马ERα水平的增加是否差异 影响高脂肪或对照饮食的老年女性的记忆和海马体。第三次实验 目的是使用血管紧张素II依赖性高血压大鼠模型，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产生影响;和B）确定 如果海马ERα水平的增加对老年女性的记忆和海马有不同的影响， 没有或没有高血压。结果将决定在何种条件下雌激素治疗提供 有益的影响，脑介导的认知轨迹，一个决定的影响， 预防或延迟与衰老相关的记忆障碍，包括阿尔茨海默病和相关的 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.