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：
10166202
负责人：
Silvia Fossati
金额：
$ 3.56万
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 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10166202
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 Impairment 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 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 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.

项目概要/摘要大脑血管系统的损伤会导致阿尔茨海默病 (AD) 和痴呆症。除了脑淀粉样血管病 (CAA) 之外，超过 90% 的 AD 患者和许多患者都存在这种病对于认知能力正常的老年人，慢性心血管 (CV) 危险因素也会损害大脑然而，CAA 和慢性 CV 危险因素的相互作用性质。它们导致脑血管功能障碍和认知能力下降的机制尚不清楚我们的初步工作确定了β淀粉样蛋白（Aβ）介导的分子机制。我们建议阐明 Aβ 与过度表达/激活之间的相互作用。 TRAIL（TNF 相关凋亡诱导配体）死亡受体 (DR) DR4 和 DR5，未探索的靶标 DR 激活对细胞应激/死亡产生巨大影响，引发线粒体功能障碍，释放 pro- 有趣的是，细胞凋亡因子和活性氧（ROS）与慢性心血管危险因素有关。脑血管病理学，例如灌注不足、高血压和高同型半胱氨酸血症（HHC），导致类似的 EC 死亡和线粒体功能障碍途径。我们将检验以下假设：慢性心血管危险因素，如高血压、HHC 和灌注不足，可协同增强脑血管 Aβ 在 CAA 中的作用，增强 TRAIL DR 激活和线粒体功能障碍脑内皮细胞，从而导致阿尔茨海默病中的神经血管单元衰竭。目标1，在体外使用人脑内皮细胞，我们将检验慢性心血管危险因素的假设增加内皮对 Aβ 的脆弱性，增强 DR 和线粒体介导的途径。分析低灌注和 HHC 对 Aβ 介导的内皮 DR 激活的相对贡献，通过分子、生化和成像方法研究线粒体毒性和 BBB 通透性。我们将在体内测试慢性心血管危险因素增强 DR 和线粒体介导的假设淀粉样变性小鼠模型中的内皮功能障碍并增加脑血管淀粉样蛋白负荷，我们将在 Tg2576 小鼠中评估这些机制。在发生 CAA 之前或之后暴露于慢性 CV 危险因素（高血压或 HHC）。检查这些应激途径对 BBB 功能障碍、微出血、淀粉样蛋白沉积、在目标 3 中，我们将检验操纵神经免疫激活和认知功能的假设。减少 DR 激活（DR 沉默）和线粒体功能障碍（碳酸酐酶抑制剂）将预防或逆转 Aβ 与慢性药物联合诱导的内皮损伤和 BBB 通透性这项研究将揭示可改变的分子机制。潜在的混合性脑血管疾病和痴呆，对临床实践和治疗产生巨大影响公共卫生。