Mechanism of Vascular Impairment in Neurocognitive Disorders

神经认知障碍中血管损伤的机制

• 批准号: 10553093
• 负责人: Avtar K Singh
• 金额: --
• 依托单位: RALPH H JOHNSON VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10553093
• 关键词: Age; Alzheimer' s Disease; Alzheimer' s disease patient; American; Amyloid; Animal Model; Attention; Biological Markers; Blood; Blood - brain barrier anatomy; Blood Vessels; Blood brain barrier dysfunction; Brain; Brain Diseases; Brain Pathology; Catabolism; Cell Culture Techniques; Cerebral Amyloid Angiopathy; Cerebrovascular Circulation; Cerebrum; Chronic; Cognition; Complex; Dementia; Disease; Drug Targeting; Elderly; Endothelial Cells; Endothelium; Enzymes; Etiology; Expectancy; F-Actin; Functional disorder; Genetic; Goals; Health; Heart Diseases; Hemorrhage; Homeostasis; Human; Hypertension; Impaired cognition; Impairment; Inflammation; Investigation; Ischemia; Knockout Mice; Laboratories; Maintenance; Mediating; Metabolic; Metabolic syndrome; Metabolism; Mission; Mutant Strains Mice; N,N-dimethylarginine; NOS3 gene; Neurocognitive; Neurons; Nitric Oxide; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Oxidation-Reduction; Pathogenesis; Pathologic; Pathology; Peroxonitrite; Play; Population; Production; Proteins; Regulation; Reporting; Research; Risk Factors; Role; S-Nitrosoglutathione; Stress Fibers; Study models; Syndrome; Therapeutic; Transgenic Mice; United States Department of Veterans Affairs; Validation; Vascular Diseases; Vascular Endothelium; Veterans; abeta deposition; age related; aged; blood-brain barrier disruption; blood-brain barrier function; cerebral hypoperfusion; cerebral microvasculature; design; dimethylargininase; early onset; endothelial dysfunction; hemodynamics; hypoperfusion; inhibitor; insight; mouse model; mutant; neurocognitive disorder; neuroinflammation; neurovascular; nitrosative stress; pharmacologic; therapeutic target; vascular cognitive impairment and dementia; wasting

Vascular cognitive impairment and dementia (VCID) is the most common etiology of dementia in the elderly including veterans. Since proportion of the elderly population is progressively increasing, VCID has become a significant problem for elderly citizens, especially veterans. Therefore, the study of this disease is relevant to veterans’ health and thus the mission of the Veterans Administration. VCID involves multiple risk factors, such as hypertension, cardiac disease, obesity, and type 2 diabetes mellitus (T2DM). Over 40 million Americans aged 70 years or older have at least one of these metabolic risk factors, yet we know relatively little about how these risk factors contribute to VCID. Recently, elevation of asymmetric dimethylarginine (ADMA) in blood has gained attention as a biomarker and a risk factor for vascular disease. ADMA catabolism is reduced by decreased expression/activity of its catabolic enzyme dimethylarginine dimethylaminohydrolase (DDAH) under conditions of vascular disease. Secondly, DDAH dysfunction and ADMA elevation contribute to dysfunction of endothelial nitric oxide (NO) synthase (eNOS) leading to vascular and endothelial disease. ADMA uncouples eNOS leading to dysfunction of redox- based NO metabolism with excessive production of peroxynitrite (ONOOˉ). ADMA is also reported to reduce cerebral blood flow (CBF) and blood-brain barrier (BBB) dysfunction. While decreased CBF and BBB disruption have been highly implicated in the pathogenesis of VCID, the role of ADMA in VCID-related pathogenesis, as well as underlying endothelial/vascular mechanisms are not well understood at present. Therefore, the goal of proposed study is to investigate ADMA as an intermediary mechanism between the known risk factors and VCID-related brain pathologies and to evaluate the therapeutic strategies targeting the ADMA-induced endothelial eNOS/NO dysregulation for VCID associated brain disease. To understand ADMA-mediated mechanisms in VCID, we have recently investigated the role of ADMA in vascular and neurocognitive-pathologies in a mouse model of early-onset cerebral amyloid angiopathy (CAA: Tg-SwDI). CAA is known to promote VCID through a number of mechanisms including inflammation, hypoperfusion, and loss of BBB function and integrity. From these initial investigations, we discovered that ADMA overburden during the course of CAA causes an increased BBB dysfunction, loss of brain microvessels, neuroinflammation, and cognitive decline with increased endothelial nitrosative stress. These findings led us to hypothesize that overburden of blood or brain ADMA levels, as a result of defective DDAH activity, drives VCID-related microvascular pathogenesis in the brain by disturbing the vascular/endothelial NO homeostasis. VCID is a multifactorial and complex disease. At present, therefore, there is no specific animal model that is considered as the gold standard for assessing VCID pathology and therapeutics. We propose to investigate the role of ADMA in VICD pathogenesis and underlying mechanisms using two mouse models of CAA and chronic cerebral hypoperfusion (CCH) which are the most relevant to VCID pathogenesis. Specific Aim 1: To investigate the role of impaired ADMA catabolism in VCID-related pathologies: Studies are proposed to assess the role of ADMA overburden and DDAH dysfunction as disease modifying factors and thus therapeutic targets for VCID-associated vascular and neurocognitive pathologies using the pharmacological (exogenous ADMA treatment) and genetic (use of DDAH1-Tg and DDAH1-Ko mice) approaches. Specific Aim 2: To investigate the role of imbalanced NO metabolism (ONOOˉ > GSNO) in ADMA- induced cerebro-microvascular dysfunction: Studies are designed to investigate the mechanism(s) underlying ADMA-induced dysregulation of eNOS activity in brain microvessels and associated vascular disease, specifically, the role of ADMA in imbalance of NO metabolism to ONOOˉ vs. S-nitrosoglutathione (GSNO), which play opposing roles in maintenance of brain microvessel endothelial barrier integrity.

血管性认知损害和痴呆(VCID)是老年人痴呆最常见的病因 包括退伍军人。随着老年人口比例的逐步增加，VCID已成为一种 对于老年人，特别是退伍军人来说，这是一个重大问题。因此，对该病的研究具有重要意义。 退伍军人的健康，因此是退伍军人管理局的使命。VCID涉及多个风险因素，如 如高血压、心脏病、肥胖和2型糖尿病(T2 DM)。4000多万美国人 70岁或70岁以上的人至少有一种代谢风险因素，但我们对这些因素是如何产生的知之甚少 这些风险因素促成了VCID的发生。 近年来，血液中不对称二甲基精氨酸(ADMA)的升高作为一种生物标志物和 血管疾病的危险因素。ADMA分解代谢因其分解代谢的表达/活性降低而减少 血管疾病条件下的二甲基精氨酸二甲氨基水解酶(DDAH)。第二， DDAH功能障碍和ADMA升高参与内皮型一氧化氮合酶功能障碍 (ENOS)导致血管和内皮疾病。ADMA解偶联eNOS导致氧化还原功能障碍 以过量产生过氧亚硝酸盐(ONOOˉ)为基础的NO代谢。据报道，ADMA也会减少 脑血流(CBF)和血脑屏障(BBB)障碍。同时减少CBF和BBB干扰 与VCID的发病密切相关，ADMA在VCID相关的发病机制中的作用，AS 以及潜在的内皮/血管机制目前还不清楚。因此，目标是 建议的研究是调查ADMA作为已知风险因素和 VCID相关脑病理及针对ADMA诱导的治疗策略评价 血管内皮细胞eNOS/NO失衡与VCID相关性脑病 为了了解ADMA在VCID中的介导机制，我们最近研究了ADMA在VCID中的作用 早发性脑淀粉样血管病小鼠模型的血管和神经认知病理学(CAA： TG-Swdi)。已知CAA通过一系列机制促进VCID，包括炎症， 低灌注率，血脑屏障功能和完整性丧失。从这些初步调查中，我们发现， CAA过程中ADMA负荷过重导致血脑屏障功能障碍增加，脑微血管丢失， 神经炎症，认知能力下降，内皮亚硝化应激增加。这些发现使我们 假设血液或大脑ADMA水平过重，作为DDAH活动缺陷的结果，驱动 VCID相关的脑微血管发病机制是通过扰乱血管/内皮细胞的内环境平衡来实现的。 VCID是一种多因素、复杂的疾病。因此，目前还没有特定的动物模型 被认为是评估VCID病理和治疗的金标准。我们建议调查 ADMA在VICD发病机制中的作用及其机制 慢性脑低灌注(CCH)与VCID的发病机制密切相关。 具体目标1：研究ADMA分解代谢受损在VCID相关病理中的作用：研究 建议评估ADMA过载和DDAH功能障碍作为疾病修改因素和 因此，VCID相关血管和神经认知病理的治疗靶点使用药理学 (外源ADMA治疗)和遗传(使用DDAH1-Tg和DDAH1-Ko小鼠)方法。 目的2：探讨NO代谢失衡(ONOO、ˉ、GSNO)在ADMA中的作用 诱发的脑微血管功能障碍：研究旨在探讨其机制(S) ADMA诱导的脑微血管及相关血管eNOS活性异常 疾病，具体地说，ADMA在NO代谢失衡中对ONOOˉ和S-亚硝基谷胱甘肽的作用 (GSNO)在维持脑微血管内皮细胞屏障完整性方面扮演相反的角色。