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.

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.