Psychosocial Stress-Induced Vascular Contributions To Cognitive Impairment And Alzheimer's Disease: The Role of Xanthine Oxidase

心理社会压力诱发的血管对认知障碍和阿尔茨海默病的影响：黄嘌呤氧化酶的作用

• 批准号: 10621570
• 负责人: Paul D Chantler
• 金额: $ 5.36万
• 依托单位: WEST VIRGINIA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2023-07-07
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10621570
• 关键词: 3xTg-AD mouse; Acceleration; Alzheimer' s Disease; Alzheimer' s disease diagnosis; Alzheimer' s disease model; Alzheimer' s disease pathology; American Stroke Association; Amyloid beta-Protein; Award; Blood Circulation; Blood Vessels; Cerebrovascular Disorders; Cerebrovascular system; Chronic; Chronic stress; Cognition; Common carotid artery; Data; Dementia; Dependovirus; Disease Progression; Elderly; Endothelium; Ensure; Etiology; Event; Exposure to; FDA approved; Funding; Goals; Grant; Hepatic; Hydrogen Peroxide; Impaired cognition; Individual; Inflammatory; Injections; Knockout Mice; Life; Link; Liver; Measures; Mediating; Mediator of activation protein; Modeling; Molecular; Mus; Nitric Oxide; Operative Surgical Procedures; Outcome; Oxidants; Oxidative Stress; Parents; Pathology; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Play; Pre-Clinical Model; Process; Production; Psychosocial Stress; Research; Risk Factors; Role; Scientist; Site; Source; Stress; Structure; Superoxides; TLR4 gene; Testing; Training Support; United States National Institutes of Health; Vascular Cognitive Impairment; Vascular Diseases; Work; XDH gene; Xanthine Oxidase; ameroid; artery occlusion; cerebral hypoperfusion; cerebrovascular; cerebrovascular pathology; clinical predictors; cognitive function; comorbidity; conditional knockout; endothelial dysfunction; epidemiologic data; febuxostat; gain of function; improved; loss of function; negative affect; neurovascular; novel; parent grant; prevent; tau Proteins; vascular cognitive impairment and dementia; vascular inflammation

ABSTRACT Vascular contributions to cognitive impairment and dementia (VCID) is the second leading cause of dementia behind Alzheimer's disease (AD), and is a frequent co-morbidity with AD. Furthermore, the deleterious effect of vascular pathologies combined with AD pathology leads to increased likelihood of dementia. Despite the importance of VCID, little is known about its molecular mechanisms underlying vascular and cognitive dysfunction. Chronic psychosocial stress is a risk factor of VCID. Our preliminary data showing that chronic stress leads to considerable cerebrovascular changes that have similar fundamental changes evident in the progression of AD has led us to focus on this process. Endothelial dysfunction is a critical determinant of vascular disease and predictor of clinical events. Xanthine oxidoreductase (XOR) is a major source of oxidative products (hydrogen peroxide and superoxide). The liver is the site of greatest XOR activity and the main source of circulating XOR activity. As such, XOR can negatively affect the vasculature. Our preliminary data suggest that chronic stress increases XOR activity resulting in cerebrovascular dysfunction. Our central hypothesis is XOR amplification due to stress will directly cause cerebrovascular dysfunction, leading to cognitive decline and the acceleration of dementia/AD pathology. Aim 1 uses liver-specific Xdh (HXO), vascular-specific Xdh (EndoXO), and double liver-vascular specific Xdh (H&EXO) conditional knockout models (loss of function) to identify the contribution of liver and vascular derived XOR and its actions on cerebrovascular and cognitive function. In Aim 2, we will determine the role of XOR on dementia/AD pathology and progression. We will: 1) use our Xdh (liver, vascular, liver & vascular) conditional knockout models (loss of function) combined with a model of VCID (asymmetric common carotid artery occlusion surgery with an ameroid constrictor, ACAS), to induce chronic cerebral hypoperfusion; and 2) in our 3xTg-AD mice we will block XOR production (with Febuxostat; loss of function) and increase XOR activity with our XDH adeno-associated virus (AAV; gain of function). These models will allow us to directly test the role of XOR and its actions on cerebrovascular and cognitive function. As with aim 1, I will measure cerebrovascular function and structure, oxidative products, cognitive function, and other AD-related pathologies (Tau, amyloid-β etc).Thus, the overall goal of these studies is to determine the etiology of the stress-related XOR and pro-inflammatory changes in mediating VCID, and its progression to AD pathology. The studies will fill gaps identified by the NIH regarding the need for understanding of vascular contributions to cognitive impairment and dementia.

抽象的 血管对认知障碍和痴呆 (VCID) 的影响是痴呆的第二大原因 阿尔茨海默氏病 (AD) 是阿尔茨海默氏病 (AD) 的常见病，而且是 AD 的常见并发症。 尽管血管病变与 AD 病理相结合，但仍会导致痴呆的可能性增加。 VCID 的重要性，但对其血管和认知的分子机制知之甚少 慢性心理社会压力是 VCID 的一个危险因素。 压力会导致相当大的脑血管变化，这些变化在大脑中也有类似的明显变化。 AD 的研究使我们关注内皮功能障碍是血管疾病进展的关键决定因素。 黄嘌呤氧化还原酶 (XOR) 是氧化产物的主要来源。 （过氧化氢和超氧化物）肝脏是 XOR 活性最强的部位，也是 XOR 的主要来源。 因此，XOR 会对脉管系统产生负面影响。 慢性压力会增加 XOR 活性，导致脑血管功能障碍。我们的中心假设是 XOR。 压力放大会直接引起脑血管功能障碍，导致认知能力下降 目标 1 使用肝脏特异性 Xdh (HXO)、血管特异性 Xdh。 (EndoXO) 和双肝血管特异性 Xdh (H&EXO) 条件敲除模型（功能丧失） 确定肝脏和血管衍生的 XOR 的贡献及其对脑血管和认知的作用 在目标 2 中，我们将确定 XOR 在痴呆/AD 病理学和进展中的作用。 我们的 Xdh（肝脏、血管、肝脏和血管）条件敲除模型（功能丧失）与模型相结合 VCID（使用 ameroid 缩窄器进行不对称颈总动脉闭塞手术，ACAS），以诱导 慢性脑灌注不足；2) 在我们的 3xTg-AD 小鼠中，我们将阻断 XOR 的产生（使用非布索坦；损失） 功能）并增加与我们的 XDH 腺相关病毒（AAV；功能获得）的 XOR 活性。 模型将使我们能够直接测试 XOR 的作用及其对脑血管和认知功能的作用。 目标 1，我将测量脑血管功能和结构、氧化产物、认知功能和 其他 AD 相关病理（Tau、β 淀粉样蛋白等）。因此，这些研究的总体目标是确定 应激相关 XOR 和介导 VCID 的促炎性变化的病因学及其进展为 AD 这些研究将填补 NIH 在了解血管方面的空白。 损伤和痴呆。