Potentiation of CAA-mediated endothelial dysfunction by cardiovascular risk factors

心血管危险因素增强 CAA 介导的内皮功能障碍

基本信息

批准号：
10427355
负责人：
Silvia Fossati
金额：
$ 56.06万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10427355
关键词：
Acetazolamide Address Alzheimer&apos s Disease Alzheimer&apos s disease patient Amyloid Amyloid beta-Protein Amyloid deposition Amyloidosis Animals Apoptotic Behavioral Biochemical Biological Response Modifiers Blood - brain barrier anatomy Blood Vessels Brain Brain Infarction Brain imaging Carbonic Anhydrase Inhibitors Cardiovascular system Cell Death Cells Cellular Stress Cerebral Amyloid Angiopathy Cerebrovascular Circulation Cerebrovascular Disorders Cerebrovascular system Cerebrum Cessation of life Chemicals Chemosensitization Chronic Clinical Cognitive Complex Dementia Deposition Development Elderly Endothelial Cells Endothelium Epidemiology Exposure to FDA approved Failure Functional disorder Glucose Homocysteine Human Hydrogen Peroxide Hyperhomocysteinemia Hypertension Impaired cognition In Vitro Individual Intervention Link Mediating Mediator of activation protein Methazolamide Microvascular Dysfunction Mitochondria Molecular Mus Nature Nerve Degeneration Neuroimmune Outcome Oxygen Pathogenesis Pathologic Pathway interactions Persons Phenotype Production Public Health Public Health Practice Reactive Oxygen Species Receptor Activation Risk Factors Stress TNF-related apoptosis-inducing ligand TNFRSF10A gene TNFRSF10B gene TNFSF10 gene TREM2 gene Testing Tg2576 Therapeutic Toxic effect Transport Process Vascular Cognitive Impairment Vascular Dementia Vascular Diseases Work abeta deposition base blood damage blood-brain barrier permeabilization brain dysfunction brain endothelial cell cardiovascular risk factor cerebral hypoperfusion cerebrovascular cerebrovascular amyloid cerebrovascular pathology clinical practice cognitive function cytokine endothelial dysfunction enhancing factor hypoperfusion imaging approach in vitro testing in vivo in vivo evaluation mitochondrial dysfunction mixed dementia mouse model neurovascular neurovascular unit non-demented novel overexpression prevent receptor vascular cognitive impairment and dementia β-amyloid burden

项目摘要

Project Summary/Abstract Damage to the brain vasculature significantly contributes to Alzheimer's disease (AD) and dementia. In addition to Cerebral Amyloid Angiopathy (CAA), which is present in more than 90% of AD patients and in many cognitively normal elderly people, chronic cardiovascular (CV) risk factors are also known to impair brain microvascular function. However, the interactive nature of CAA and chronic CV risk factors and the mechanisms through which they contribute to cerebrovascular dysfunction and cognitive decline are poorly understood. Our preliminary work identified molecular mechanisms responsible for amyloid beta (Aβ)-mediated brain endothelial dysfunction. We propose to clarify the interplay between Aβ and overexpression/activation of the TRAIL (TNF-related apoptosis inducing ligand) death receptors (DR) DR4 and DR5, unexplored targets of enormous impact for cell stress/death. DR activation triggers mitochondrial dysfunction, with release of pro- apoptotic factors and reactive oxygen species (ROS). Intriguingly, chronic CV risk factors associated with cerebrovascular pathology, such as hypoperfusion, hypertension and hyperhomocysteinemia (HHC), contribute to similar EC death and mitochondrial dysfunction pathways. We will test the hypothesis that chronic CV risk factors, such as hypertension, HHC, and hypoperfusion, synergistically potentiate the effects of cerebrovascular Aβ in CAA, enhancing TRAIL DR activation and mitochondrial dysfunction in cerebral endothelial cells, and thus leading to neurovascular unit failure in Alzheimer's disease. In Aim 1, using human cerebral endothelial cells in vitro, we will test the hypothesis that chronic CV risk factors increase endothelial vulnerability to Aβ, potentiating DR- and mitochondria-mediated pathways. We will analyze the relative contribution of hypoperfusion and HHC to Aβ-mediated endothelial DR activation, mitochondrial toxicity and BBB permeability through molecular, biochemical and imaging approaches. In Aim 2, we will test in vivo the hypothesis that chronic CV risk factors potentiate DR- and mitochondria-mediated endothelial dysfunction and increase cerebrovascular amyloid burden in a mouse model of amyloidosis, contributing to neurovascular and cognitive impairment. We will assess these mechanisms in Tg2576 mice exposed to chronic CV risk factors (hypertension or HHC) before or after the development of CAA. We will examine the effects of these stress pathways on BBB dysfunction, microhemorrhages, amyloid deposition, neuroimmune activation, and cognitive function. In Aim 3 we will Test the hypothesis that manipulations that decrease DR activation (DR silencing) and mitochondrial dysfunction (carbonic anhydrase inhibitors) will prevent or reverse endothelial damage and BBB permeability induced by the combination of Aβ and chronic cerebrovascular challenges that occur with CV risk. This study will reveal modifiable molecular mechanisms underlying mixed cerebrovascular disease and dementia, which have enormous impact on clinical practice and public health.

项目摘要/摘要对脑脉管系统的损害显着导致阿尔茨海默氏病（AD）和痴呆症。除脑淀粉样血管病（CAA）外，还存在于90％以上的AD患者中认知正常的人，慢性心血管（CV）风险因素也会损害大脑微血管功能。但是，CAA和慢性简历风险因素的互动性质以及它们导致脑血管功能障碍和认知能力下降的机制很差理解。我们的初步工作确定了负责淀粉样β（Aβ）介导的分子机制脑内皮功能障碍。我们建议阐明Aβ与过表达/激活之间的相互作用步道（与TNF相关的凋亡诱导配体）死亡受体（DR）DR4和DR5，意外的目标对细胞应力/死亡的巨大影响。 DR激活会触发线粒体功能障碍，并释放凋亡因子和活性氧（ROS）。有趣的是，与之相关的慢性简历风险因素脑血管病理学，例如灌注不足，高血压和高脑结合结膜血症（HHC），有助于类似的EC死亡和线粒体功能障碍途径。我们将检验以下假设慢性简历危险因素，例如高血压，HHC和灌注不足，协同潜力大脑Aβ在CAA中的影响，增强TRAIL DR激活和线粒体功能障碍在脑内皮细胞中，从而导致阿尔茨海默氏病的神经血管单位衰竭。 AIM 1，在体外使用人脑内皮细胞，我们将测试慢性简历风险因素的假设增加对Aβ的内皮脆弱性，潜在的DR-和线粒体介导的途径。我们将分析灌注灌注和HHC对Aβ介导的内皮DR激活的相对贡献，线粒体毒性和BBB渗透性通过分子，生化和成像方法。在AIM 2中，我们将在体内检验一个假说，即慢性简历危险因素潜在的DR-和线粒体介导内皮功能障碍并增加淀粉样变性小鼠模型中的脑血管淀粉样蛋白伯嫩，导致神经血管和认知障碍。我们将在TG2576小鼠中评估这些机制在CAA发展之前或之后，暴露于慢性简历危险因素（高血压或HHC）。我们将检查这些应力途径对BBB功能障碍，微毛发，淀粉样沉积，神经免疫性激活和认知功能。在AIM 3中，我们将检验以下假设。减少DR激活（DR Silencing）和线粒体功能障碍（碳酸酐酶抑制剂）将会预防或反向内皮损伤和Aβ和慢性组合引起的BBB渗透性 CV风险发生的脑血管挑战。这项研究将揭示可修改的分子机制基本的混合脑血管疾病和痴呆，对临床实践和公共卫生。