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: 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
• 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' 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 - 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

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500万老年美国人患有痴呆症，预计 由于预期寿命的增长，到2025年，新的痴呆症病例数量将翻一番。阿尔茨海默病 (AD)是老年人痴呆症最常见的原因，占所有痴呆症的80% 诊断。目前，阿尔茨海默病还没有治愈方法。因此，迫切需要新的干预措施，能够 预防发病，延缓病情进展，从而提高老年人的生活质量。 载脂蛋白E4等位基因(ApoE4)是阿尔茨海默病最常见的遗传危险因素，占AD的60% 在普通人群中，我们并不完全了解它是如何导致痴呆症的。载脂蛋白是 对脂类新陈代谢和胆固醇运输至关重要。其他已知的AD风险因素包括年龄较大， 女性，高血压。我们从人类载脂蛋白E4敲门蛋白(E4)获得的稳健的初步数据 和ApoE3敲门(E3)小鼠，表明与雄性E4小鼠相比，雌性E4小鼠发展认知能力 随着年龄的增长而下降和高血压。值得注意的是，我们发现脑脊液中血管紧张素II(AngII)的水平是兴奋性的 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 老鼠。现在越来越明显的是，血管紧张素转换酶促炎症作用破坏血脑屏障和 增加淀粉样蛋白-b和tau的负荷导致大脑空间学习和记忆区域的神经毒性， 海马区(HC)。此外，血管紧张素转换酶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驱动的炎症介导了认知功能下降和 老年高血压，ApoE4基因。一个主要的担忧是缺乏合适的小鼠 这些模型概括了人类AD的特征。因此，我们将研究表达该基因的新型转基因小鼠。 人载脂蛋白E3或载脂蛋白E4敲打蛋白基因与三种转基因(APPSW、PS1dE9和tauP301S)的结合 建立小鼠AD模型。我们将用最先进的生理学和分子生物学来检验这些新的假说 在以下两个具体目标方面采取了措施。 目的1：验证脑血管紧张素转换酶诱导的炎症导致女性认知障碍的假设 E4小鼠。 目的2：验证高血压加重雌性E4小鼠增龄后认知功能减退的假说。 这些研究将确定认知衰退的潜在中枢机制(S)，并发现新的 治疗目标(S)，将使基础科学发现转化为临床实践 阿尔茨海默病和相关痴呆症。