Discovering novel mechanisms for aging-related dementia: probing medin and abeta vasculopathy

发现衰老相关痴呆的新机制：探索医学和阿贝塔血管病

• 批准号: 9352441
• 负责人: Raymond Quezon Migrino
• 金额: --
• 依托单位: PHOENIX VA HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9352441
• 关键词: Adipose tissue; Aging; Alzheimer' s Disease; American Heart Association; Amino Acids; Amyloid; Amyloid Proteins; Amyloid beta-Protein; Amyloidosis; Animal Model; Autopsy; Biochemistry; Biological Availability; Biology; Biometry; Blood Vessels; Brain; Cerebrovascular Disorders; Clinical Data; Cognitive; Collaborations; Data; Dementia; Deposition; Disease; Elderly; Endothelial Cells; Epidemiology; Functional disorder; Funding; Goals; Health; Human; Impaired cognition; Impairment; Inflammation; Inflammatory Response; Institutes; Late Onset Alzheimer Disease; Lead; Link; Measures; Mediating; Microvascular Dysfunction; Neurosciences; Nitrates; Nitric Oxide; Oxidative Stress; Oxidative Stress Induction; Peptides; Peripheral; Population; Proteins; Recording of previous events; Research; Research Institute; Research Personnel; Resources; Role; Signal Transduction; Stress; Stroke; Testing; The Sun; Tissue Model; Tissues; Translations; United States National Institutes of Health; Vascular Dementia; Vascular Diseases; Vascular Smooth Muscle; Veterans; arteriole; base; brain tissue; cerebral hypoperfusion; cerebrovascular; cognitive function; cognitive testing; effective therapy; endothelial dysfunction; human disease; medin; multidisciplinary; neuropathology; new therapeutic target; novel; novel strategies; pre-clinical; programs; subcutaneous; vascular cognitive impairment and dementia; vascular inflammation; working group

Abstract There remains no effective treatment to reverse aging-related dementia disorders (ARDD), including Alzheimer’s disease (AD). Epidemiologic, preclinical and clinical data show that vascular disease is strongly associated with ARDD and AD and that vascular dysfunction leading to cerebral hypoperfusion is critical in the early stages of AD. Prior investigators showed that medin, a 50 amino acid peptide found in vascular smooth muscle layer, is the most common amyloid protein in humans with progressive vascular deposition with aging. Medin was implicated as a cause of vessel wall degenerative changes associated with vascular aging, but its role in aging-related cerebrovascular dysfunction is not known. We have preliminary data in both adipose and leptomeningeal arterioles that medin as well as β-amyloid (Aβ), a peptide involved in AD, induce endothelial dysfunction through oxidative stress and reduced nitric oxide bioavailability and that medin induces strong pro- inflammatory response in endothelial cells. Our overall goal is to test the hypotheses that medin amyloid protein, alone or synergistically with Aβ, is a significant, but unrecognized, cause of ARDD by inducing human brain microvascular dysfunction and inflammation. For Aim 1 we will probe the role of medin amyloid and its interaction with Aβ in causing aging-associated human cerebrovascular dysfunction and cognitive dysfunction. We will measure extent of cerebrovascular medin amyloidosis in the elderly and its relationship to cognitive dysfunction and Alzheimer’s disease using tissue and associated pre-mortem clinical data from Sun Health Research Institute Brain Donation Program. We will also probe mechanisms by which medin amyloid induces cerebrovascular dysfunction in ex-vivo rapid autopsy human brain leptomeningeal arterioles, focusing on the role of nitric oxide dysregulation, oxidative stress and induction of vascular inflammation. We will study the interaction between medin and Aβ in inducing human cerebrovascular dysfunction, vascular inflammation and cognitive dysfunction. For Aim 2, we will validate whether peripherally obtained subcutaneous adipose arterioles are useful surrogates to brain cerebrovascular arterioles in studying medin and Aβ-induced microvascular dysfunction. The proposal will have impact in the potential discovery of a novel mechanism that could link vascular aging and cognitive dysfunction in the elderly. Furthermore, the use of a novel and unique human brain tissue model would enhance the translation relevance of the findings to the human condition.

抽象的 尚无对逆向衰老相关痴呆疾病（ARDD）的有效治疗，包括 阿尔茨海默氏病（AD）。流行病学，临床前和临床数据表明，血管疾病强烈 与ARDD和AD相关，以及导致脑部灌注灌注障碍的血管功能障碍对 广告的早期阶段。先前的研究者表明，在血管光滑中发现的50个氨基酸肽Medin 肌肉层是人类中最常见的淀粉样蛋白，具有衰老的进行性血管沉积。 Medin被实施是与血管衰老相关的血管壁变性的原因，但 在与衰老相关的脑血管功能障碍中的作用尚不清楚。我们在脂肪和 脑膜脑脑脑动脉和β-淀粉样蛋白（Aβ），参与AD的肽，诱导内皮 通过氧化应激和一氧化氮生物利用度降低的功能障碍，而Medin诱导了强大的促进症 内皮细胞中的炎症反应。我们的总体目标是测试Medin淀粉样蛋白的假设 蛋白质单独或与Aβ协同作用，是一种显着但无法识别的蛋白质，原因是ARDD的原因是 脑微血管功能障碍和炎症。对于AIM 1，我们将探究Medin淀粉样蛋白及其的作用 与Aβ的相互作用在引起与衰老相关的人脑功能障碍和认知功能障碍时的相互作用。 我们将衡量脑血管中的脑血管淀粉样变性及其与认知的关系 使用组织和相关验尸临床数据的功能障碍和阿尔茨海默氏病 研究机构大脑捐赠计划。我们还将探测Medin淀粉样蛋白影响的机制 前体内快速尸检人脑脑脑膜动脉脑血管功能障碍，重点是 一氧化氮失调，氧化应激和血管注射诱导的作用。我们将研究 在诱导的人脑功能障碍，血管注射和Aβ之间的相互作用，血管注射和 认知功能障碍。对于AIM 2，我们将验证外围获得的皮下脂肪是否 小动脉在研究MEDIN和Aβ诱导的 微血管功能障碍。该提议将影响潜在的发现一种新机制 可以将血管衰老和认知功能障碍链接起来。此外，使用小说和独特 人脑组织模型将增强发现结果与人类状况的翻译相关性。