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.

血管性认知障碍和痴呆（VCID）是老年人痴呆最常见的病因 包括退伍军人。随着老年人口比例逐渐增加，VCID已成为 对于老年人，尤其是退伍军人来说，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，从而也是退伍军人管理局的使命。 VCID 涉及多种风险因素，例如 如高血压、心脏病、肥胖和 2 型糖尿病 (T2DM)。超过 4000 万美国人 70 岁或以上的老年人至少有其中一种代谢危险因素，但我们对其如何影响知之甚少 这些风险因素会导致 VCID。 最近，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而受到关注 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 升高导致内皮一氧化氮 (NO) 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 基于NO代谢并过量产生过氧亚硝酸盐（ONOOˉ）。据报道，ADMA 也将减少 脑血流（CBF）和血脑屏障（BBB）功能障碍。同时减少 CBF 和 BBB 破坏 与 VCID 的发病机制密切相关，ADMA 在 VCID 相关发病机制中的作用，如 目前尚不清楚潜在的内皮/血管机制。因此，目标是 拟议的研究旨在调查 ADMA 作为已知风险因素和风险因素之间的中介机制。 VCID 相关的脑部病理学并评估针对 ADMA 诱导的治疗策略 VCID 相关脑部疾病的内皮 eNOS/NO 失调。 为了了解 VCID 中 ADMA 介导的机制，我们最近研究了 ADMA 在 早发性脑淀粉样血管病小鼠模型中的血管和神经认知病理学（CAA： Tg-SwDI)。众所周知，CAA 可通过多种机制促进 VCID，包括炎症、 灌注不足，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 负担过重，导致 BBB 功能障碍增加、脑微血管丧失、 内皮亚硝化应激增加导致神经炎症和认知能力下降。这些发现引导我们 假设 DDAH 活性缺陷导致血液或大脑 ADMA 水平负担过重，导致 VCID 相关的大脑微血管发病机制是通过扰乱血管/内皮 NO 稳态来实现的。 VCID 是一种多因素、复杂的疾病。因此，目前尚无特定的动物模型 被认为是评估 VCID 病理学和治疗的金标准。我们建议调查 使用 CAA 和 CAA 两种小鼠模型研究 ADMA 在 VICD 发病机制中的作用和潜在机制 慢性脑灌注不足（CCH）与 VCID 发病机制最相关。 具体目标 1：调查 ADMA 分解代谢受损在 VCID 相关病理中的作用：研究 建议评估 ADMA 超负荷和 DDAH 功能障碍作为疾病调节因素的作用， 因此，使用药理学方法治疗 VCID 相关血管和神经认知病理学的目标 （外源性 ADMA 治疗）和遗传（使用 DDAH1-Tg 和 DDAH1-Ko 小鼠）方法。 具体目标 2：研究不平衡的 NO 代谢 (ONOOˉ > GSNO) 在 ADMA-中的作用 诱发脑微血管功能障碍：研究旨在调查其机制 ADMA 诱导的脑微血管和相关血管中 eNOS 活性的潜在失调 疾病，特别是 ADMA 在 ONOOˉ 与 S-亚硝基谷胱甘肽的 NO 代谢失衡中的作用 （GSNO），在维持脑微血管内皮屏障完整性方面发挥相反作用。