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。

• 批准号: 10301248
• 负责人: Rasna Sabharwal
• 金额: $ 23.18万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10301248
• 关键词: 5 year old; Affect; Age; Age-associated memory impairment; Aging; Alleles; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Alzheimer’s disease biomarker; American; Amyloid beta-Protein; Angiotensin II; Antihypertensive Agents; Apolipoprotein E; Backcrossings; Basic Science; Blood; 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; Neurofibrillary Tangles; Pathogenesis; Pathology; Peptide Receptor; Peptides; 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; 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/antagonist; 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

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.

项目摘要/摘要 在美国，至少有五百万年长的美国人患有痴呆症，预计 由于预期寿命的增长，到2025年，新的痴呆症病例的数量将翻一番。阿尔茨海默氏病 （AD）是古老的痴呆症最常见原因，最多占所有痴呆症的80％ 诊断。目前，无法治愈广告。那迫切需要新的干预措施 防止发作和减慢疾病的进展，从而改善了较早的生活质量。 载脂蛋白E4等位基因（APOE4）是AD的最普遍的遗传危险因素，占AD的60％ 一般人群中的受试者，但我们不完全了解它如何引起痴呆症。 Apoe蛋白是 对于脂质代谢和胆固醇运输至关重要。广告的其他已知风险因素包括年龄较大， 女性和高血压。我们从人类APOE4-KNOCKIN获得的强大初步数据（E4） 和ApoE3-Knockin（E3）小鼠，与雄性相比，雌性E4小鼠会发展认知 衰老的衰落和高血压。值得注意的是，我们发现CSF水平的血管紧张素II（Angii），兴奋性 脑肾素 - 血管紧张素系统（RAS）的成分，雌性E4的年龄逐渐增加 老鼠。现在正在证明Angii的促炎作用损害了血脑屏障和 增加淀粉样蛋白B和TAU负荷，导致神经毒性在大脑的空间学习和记忆区域中， 海马（HC）。此外，在大脑心血管区域中通过1型受体作用的Angii， 下丘脑（PVN）的室室核调节动脉血压和自主功能。 这就是我们的核心假设是，大脑RAS驱动的炎症介导了认知能力下降和 APOE4基因型中衰老中的高血压。一个主要问题是缺乏适当的鼠 概括人类广告标志的模型。因此，我们将研究表达的新型转基因小鼠 人类APOE3或APOE4敲击基因与三个转基因（AppSw，ps1de9和Taup301s）结合在一起 小鼠中的模型广告。我们将用最先进的生理和分子测试新假设 在以下两个具体目标中的方法。 目的1：检验以下假设：脑RAS诱导的感染驱动女性认知障碍 E4小鼠。 目的2：检验以下假设：高血压加剧了随着年龄的增长的女性E4小鼠的认知下降。 这些研究将定义衰老认知能力下降的基本中心机制并确定新颖 治疗目标将使基础科学的发现能够转化为临床实践 阿尔茨海默氏病和相关痴呆症。