RAS-Driven Central Inflammation and Cognitive Decline with Aging.

RAS 驱动的中枢炎症和认知能力随着衰老而下降。

基本信息

批准号：
10453781
负责人：
Rasna Sabharwal
金额：
$ 19.31万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10453781
关键词：
5 year old Affect Age Age-associated memory impairment Aging Alleles Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease related dementia Alzheimer&apos s disease risk Alzheimer’s disease biomarker American Amyloid beta-Protein Angiotensin II Antihypertensive Agents Apolipoprotein E Backcrossings Basic Science Blood - brain barrier anatomy Blood Pressure Brain Brain region Cardiovascular system Cell Nucleus Censuses Cholesterol Cognition Cognitive Data Dementia Development Diagnosis Disease Disease Progression Elderly Family Female Functional disorder Gender General Population Genes Genotype Gliosis Goals Growth Hand Hippocampus (Brain)Human Hyperlipidemia Hypertension Hypothalamic structure Impaired cognition Inflammation Inflammation Mediators Inflammatory Intervention Knock-in Learning Life Expectancy Link Lipoprotein (a)Measures Mediating Memory Molecular Mouse Strains Mus Nerve Degeneration Neurofibrillary Tangles Pathogenesis Pathology Peptide Receptor Peptides Persons Physiological Population Predisposition Preventive measure Protein Isoforms Proteins Quality of life Reactive Oxygen Species Receptor Signaling Receptor, Angiotensin, Type 1 Recording of previous events Renin-Angiotensin System Research Rest Risk Factors Role Signal Transduction Testing Transgenes Transgenic Mice Translating United States Woman age related aging hippocampus antagonist apolipoprotein E-4 behavior test blood damage clinical practice comorbidity dementia risk genetic risk factor genetic variant genome wide association study global health human old age (65+)improved inhibitor interest lipid metabolism male middle age modifiable risk mouse model neuroinflammation neuron loss neurotoxicity new therapeutic target novel novel therapeutic intervention paraventricular nucleus prevent receptor receptor expression sex tau Proteins tau mutation

项目摘要

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.

项目概要/摘要在美国，至少有 500 万美国老年人患有痴呆症，预计由于阿尔茨海默病预期寿命的延长，到 2025 年，新发痴呆病例数量将增加一倍。 (AD) 是老年人痴呆症的最常见原因，占所有痴呆症的 80% 目前，AD 尚无治愈方法，因此迫切需要新的干预措施。预防发病并减缓疾病进展，从而提高老年人的生活质量。载脂蛋白 E4 等位基因 (ApoE4) 是 AD 最常见的遗传风险因素，占 AD 的 60% 普通人群中的受试者，但我们还不完全了解 ApoE 蛋白是如何导致痴呆的。对于脂质代谢和胆固醇转运至关重要其他已知的 AD 风险因素包括年龄较大、我们从人类 ApoE4 基因敲入 (E4) 中获得了可靠的初步数据。和 ApoE3 敲入 (E3) 小鼠，证明与雄性相比，雌性 E4 小鼠具有认知能力值得注意的是，我们发现脑脊液中兴奋性血管紧张素 II (AngII) 的水平。大脑肾素-血管紧张素系统 (RAS) 的组成部分，在女性 E4 中随着年龄的增长而逐渐增加现在越来越明显的是，AngII 的促炎作用会损害血脑屏障和增加淀粉样蛋白-b 和 tau 蛋白负荷，导致大脑空间学习和记忆区域的神经毒性，此外，AngII 通过大脑心血管区域的 1 型受体发挥作用，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和老年高血压中 ApoE4 基因型的一个主要问题是缺乏合适的小鼠。因此，我们将研究表达人类 AD 特征的新型转基因小鼠。人 ApoE3 或 ApoE4 敲入基因与三种转基因（APPSW、PS1dE9 和 tauP301S）相结合，我们将用最先进的生理学和分子学方法来测试新的假设。采取以下两个具体目标。目标 1：检验大脑 RAS 诱导的炎症导致女性认知障碍的假设 E4小鼠。目标 2：检验高血压会导致雌性 E4 小鼠随着年龄增长而认知能力下降的假设。这些研究将定义衰老过程中认知能力下降的潜在中心机制，并确定新的机制。能够将基础科学的发现转化为临床实践的治疗目标阿尔茨海默病和相关痴呆症。