RAS-Driven Central Inflammation and Cognitive Decline with Aging.

项目总结/摘要 在美国，至少有500万美国老年人患有痴呆症，据预测， 到2025年，由于预期寿命的增长，新的痴呆症病例将增加一倍。阿尔茨海默病 (AD)是老年痴呆症最常见的原因，占所有痴呆症的80% 诊断。目前还没有治愈AD的方法。因此，迫切需要新的干预措施， 预防发病，延缓病情发展，从而提高老年人的生活质量。 载脂蛋白E4等位基因（ApoE 4）是AD最常见的遗传危险因素，占AD的60 在一般人群中的受试者，但我们并不完全了解它是如何导致痴呆症的。ApoE蛋白是 对脂质代谢和胆固醇运输至关重要。AD的其他已知风险因素包括年龄较大， 女性和高血压。我们从人ApoE 4-敲入（E4）中获得的可靠的初步数据 和ApoE 3-敲入（E3）小鼠，表明与雄性相比，雌性E4小鼠发展认知能力， 衰老性高血压。值得注意的是，我们发现CSF中的血管紧张素II（AngII）水平， 在女性E4中，脑肾素-血管紧张素系统（RAS）的组分随年龄的增长而逐渐增加 小鼠现在越来越明显的是，AngII的促炎作用损害血脑屏障， 增加淀粉样蛋白-B和tau负荷导致大脑空间学习和记忆区域的神经毒性， 海马（HC）。此外，AngII通过脑心血管区域中的1型受体起作用， 下丘脑室旁核（PVN）调节动脉血压和自主神经功能。 因此，我们的中心假设是，大脑RAS驱动的炎症介导认知能力下降， 老年高血压，在ApoE 4基因型。一个主要的问题是缺乏适当的鼠 这些模型概括了人类AD的特征。因此，我们将研究新的转基因小鼠， 人ApoE 3或ApoE 4敲入基因与三种转基因（APPSW、PS1 dE 9和tauP 301 S）组合， 小鼠AD模型。我们将用最先进的生理学和分子生物学技术来检验新的假设。 在以下两个具体目标的方法。 目的1：验证RAS诱导的炎症反应导致女性认知功能障碍的假设 E4小鼠。 目的2：验证高血压加剧雌性E4小鼠认知能力随年龄增长而下降的假设。 这些研究将确定衰老中认知能力下降的潜在中枢机制，并确定新的 治疗目标，使基础科学的发现能够转化为临床实践， 阿尔茨海默氏病及相关痴呆症。

PROJECT SUMMARY/ABSTRACT In the United States, at least five million elderly Americans suffer from dementias, and it is projected that the number of new dementia cases will double by 2025 due to the growth in life expectancy. Alzheimer’s disease (AD) is the most common cause of dementia in the elderly and accounts for up to 80% of all dementia diagnoses. Currently, there is no cure for AD. Thus, there is an urgent need for novel interventions that can prevent onset and slow the disease progression, thereby improving the quality of life in the elderly. Apolipoprotein E4 allele (ApoE4) is the most prevalent genetic risk factor for AD and represents 60% of AD subjects in the general population, yet we do not fully understand how it causes dementia. ApoE protein is critical for lipid metabolism and cholesterol transport. The other known risk factors for AD include older age, female gender, and hypertension. Our robust preliminary data obtained from the human ApoE4-knockin (E4) and ApoE3-knockin (E3) mice, demonstrates that compared to the males, female E4 mice develop cognitive decline and hypertension with aging. Notably, we find CSF levels of angiotensin II (AngII), the excitatory component of the brain renin-angiotensin system (RAS), progressively increase with age in the female E4 mice. It is now becoming evident that the proinflammatory actions of AngII damage the blood-brain-barrier and increase amyloid-b and tau load causing neurotoxicity in spatial learning and memory region of the brain, the hippocampus (HC). Moreover, AngII acting via type 1 receptors in a cardiovascular region of the brain, paraventricular nucleus of hypothalamus (PVN), regulates arterial blood pressure and autonomic function. Thus, our central hypothesis is that brain RAS-driven inflammation mediates cognitive decline and hypertension in aging, in the ApoE4 genotype. A major concern has been the lack of appropriate murine models that recapitulate hallmarks of human AD. Hence we will study novel transgenic mice that express the human ApoE3 or ApoE4 knockin gene combined with three transgenes (APPSW, PS1dE9, and tauP301S) that model AD in the mice. We will test the novel hypotheses with state-of-the art physiological and molecular approaches in the following two specific aims. Aim 1: To test the hypothesis that brain RAS-induced inflammation drives cognitive impairment in female E4 mice. Aim 2: To test the hypothesis that hypertension exacerbates cognitive decline in female E4 mice with age. These studies will define underlying central mechanism(s) of cognitive decline in aging and identify novel therapeutic target(s) that will enable discoveries from basic science to be translated into clinical practice for Alzheimer’s disease and related dementias.