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 目前尚无有效的治疗方法可以逆转与衰老相关的痴呆症（ARDD），包括 阿尔茨海默病 (AD) 的流行病学、临床前和临床数据表明，血管疾病是一种严重的疾病。 与 ARDD 和 AD 相关，并且导致脑灌注不足的血管功能障碍在 先前的研究人员表明，medin 是一种在血管平滑肌中发现的 50 个氨基酸肽。 肌肉层，是人类中最常见的淀粉样蛋白，随着年龄的增长，血管会逐渐沉积。 Medin 被认为是与血管老化相关的血管壁退行性变化的原因之一，但其 我们在脂肪和脑血管功能障碍中的作用尚不清楚。 软脑膜小动脉与 β-淀粉样蛋白 (Aβ)（一种参与 AD 的肽）一起诱导内皮细胞 通过氧化应激和减少一氧化氮生物利用度而导致功能障碍，并且药物诱导强烈的亲 我们的总体目标是检验淀粉样蛋白的作用的假设。 蛋白质，单独或与 Aβ 协同作用，是导致 ARDD 的一个重要但未被认识的原因，它通过诱导人类 对于目标 1，我们将探讨 medin 淀粉样蛋白及其作用。 与 Aβ 相互作用导致衰老相关的人类脑血管功能障碍和认知功能障碍。 我们将测量老年人脑血管淀粉样变性的程度及其与认知的关系 使用来自 Sun Health 的组织和相关死前临床数据来研究功能障碍和阿尔茨海默病 我们还将探讨 Medin 淀粉样蛋白诱导的机制。 离体快速尸检人脑软脑膜小动脉的脑血管功能障碍，重点关注 我们将研究一氧化氮失调、氧化应激和诱导血管炎症的作用。 medin 与 Aβ 相互作用诱导人脑血管功能障碍、血管炎症和 对于目标 2，我们将验证是否通过外周获得皮下脂肪。 在研究 medin 和 Aβ 诱导的过程中，小动脉是脑脑血管小动脉的有用替代物 该提案将对新机制的潜在发现产生影响。 可能将老年人的血管老化和认知功能障碍联系起来。 人类脑组织模型将增强研究结果与人类状况的转化相关性。