Cerebrovascular Remodeling and Neurodegenerative Changes in Alzheimer's Disease

项目概要 阿尔茨海默氏病是痴呆症最常见的原因，也是第六大常见死因，折磨着人们 美国有近600万人。阿尔茨海默病是我们社会的主要经济负担 每年花费超过2500亿美元。脑血管完整性对于正常代谢和灌注至关重要 大脑的。大脑动脉的顺应性至关重要，因为这些动脉会抑制脉动压力和 保护微循环和血脑屏障免受损害。脑血管功能障碍可有 对大脑产生有害影响。越来越多的证据表明，脑血管功能障碍起着至关重要的作用。 在阿尔茨海默氏病的发病机制中发挥作用，并有可能用作临床前的生物标志物 阿尔茨海默病。该项目的总体目标是揭示脑血管与脑血管之间的密切关系。 重塑和阿尔茨海默病的进展。 我们的初步研究表明，随着阿尔茨海默病的病理进展，人类 脑动脉表现出进行性硬化、结构破坏，并且平滑肌细胞萎缩增加。 因此，我们假设大脑血管的结构和功能变化与 神经退行性变、β-淀粉样蛋白、其他有毒代谢物和大脑中 tau 蛋白病理的积累。 基于我们在血管力学生物学、精密质谱学方面的多学科专业知识， 先进的光学成像、免疫组织化学、血管生物学和阿尔茨海默病的神经病理学， 我们将通过三个目标来检验这一假设： 目标 1) 确定脑血管重塑（生物力学、 阿尔茨海默病患者额叶和颞叶的结构和成分变化；目标 2) 确定脑血管重塑与阿尔茨海默病病理变化之间的关联 在大脑的额叶和颞叶；目标 3) 检查脑血管之间的关联 重塑和生前认知状态以及神经心理学测试表现。 我们将使用来自 100 个年龄和性别匹配的大脑的无动脉粥样硬化或低动脉粥样硬化脑血管和脑组织 来自 NIA 资助的 BU 阿尔茨海默病研究中心的捐赠者 1) 没有阿尔茨海默病病理学， 2) 低阿尔茨海默病病理学，以及 3) 中/高阿尔茨海默病病理学 。这些 大脑 捐助者已完成年度国家阿尔茨海默病协调中心统一数据集评估 生活并有可用的基于共识的认知诊断。该提案旨在利用现有 资源来进行新的发现。脑血管和脑组织的匹配和平行研究将 为脑血管重塑和 AD 的时间发展提供新的理解。理解 血管重塑在阿尔茨海默病中的作用可能会导致新的治疗方案的发现和 预防阿尔茨海默病的干预措施的指导。

PROJECT SUMMARY Alzheimer’s disease, the most common cause of dementia and the sixth most common cause of death, afflicts nearly 6 million people in the United States. Alzheimer’s disease is a major economic burden to our society with an annual cost of more than $250 billion. Cerebrovascular integrity is critical for proper metabolism and perfusion of the brain. Compliance of large cerebral arteries is critical as these arteries dampen the pulsatile pressure and protect the microcirculation and blood brain barrier from damage. Cerebrovascular dysfunction can have detrimental impacts on the brain. Growing evidences suggest that cerebrovascular dysfunction plays a crucial role in the pathogenesis of Alzheimer’s disease and can potentially be used as a biomarker for preclinical Alzheimer’s disease. The overall goal of this project is to unravel the close relationship between cerebrovascular remodeling and the progression of Alzheimer’s disease. Our preliminary study suggested that with pathological progression of Alzheimer’s disease, the human cerebral artery showed progressive stiffening, structural breakdown, and increases smooth muscle cell atrophy. We thus hypothesize that the structural and functional changes in large cerebrovasculature is correlated with neurodegeneration and the accumulation of Amyloid-β, other toxic metabolites, and tau pathology in the brain. Building upon our multidisciplinary expertise in vascular mechanobiology, precision mass spectrometry, advanced optical imaging, immunohistochemistry, vascular biology and neuropathology of Alzheimer’s disease, we will test this hypothesis in three aims: Aim 1) to determine cerebrovascular remodeling (biomechanical, structural, and compositional changes) in the frontal and temporal lobes in Alzheimer’s disease; Aim 2) to determine the association between cerebrovascular remodeling and Alzheimer’s disease pathological changes in the frontal and temporal lobes of the brain; and Aim 3) to examine the association between cerebrovascular remodeling and antemortem cognitive status and neuropsychological test performance. We will use no or low atherosclerotic cerebrovascular and brain tissue from 100 age- and sex-matched brain donors from the NIA-funded BU Alzheimer’s Disease Research Center with 1) no Alzheimer’s disease pathology, 2) low Alzheimer’s disease pathology, and 3) intermediate/high Alzheimer’s disease pathology . These brain donors have completed annual National Alzheimer’s Coordinating Center Uniform Data Set evaluations during life and have available consensus-based cognitive diagnoses. This proposal is designed to leverage existing resources to make new discoveries. The matched and parallel studies of cerebral vessels and brain tissue will provide new understandings of the temporal development of cerebrovascular remodeling and AD. Understanding the role of vascular remodeling in Alzheimer’s disease may lead to the discovery of new treatment options and directions for interventions to stave off Alzheimer’s disease.