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.

摘要