Cerebrovascular Remodeling and Neurodegenerative Changes in Alzheimer's Disease

项目总结 阿尔茨海默氏症是导致痴呆症的最常见原因，也是第六大最常见的死亡原因， 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 每年的成本超过2500亿美元。脑血管的完整性对于正确的新陈代谢和灌流至关重要。 大脑的一部分。大脑大动脉的顺应性是至关重要的，因为这些动脉抑制脉动压力和 保护微循环和血脑屏障免受损害。脑血管功能障碍可能有 对大脑有害的影响。越来越多的证据表明，脑血管功能障碍在 在阿尔茨海默病发病机制中的作用，并可作为临床前的生物标志物 阿尔茨海默氏症。这个项目的总体目标是解开脑血管之间的密切关系 阿尔茨海默病的重塑和进展。 我们的初步研究表明，随着阿尔茨海默病的病理进展，人类 脑动脉表现为进行性硬化、结构破坏、平滑肌细胞萎缩加重。 因此，我们假设大脑血管的结构和功能变化与 神经变性和淀粉样蛋白-β、其他有毒代谢物的积累，以及大脑中的tau病理。 基于我们在血管机械生物学、精密质谱学、 阿尔茨海默病的先进光学成像、免疫组织化学、血管生物学和神经病理学， 我们将从三个方面检验这一假说：目的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)；目的2)到 确定脑血管重构与阿尔茨海默病病理改变的关系 在大脑的额叶和颞叶；以及目的3)检查脑血管与 重塑与生前认知状态和神经心理测试表现。 我们将使用100个年龄和性别匹配的无或低动脉粥样硬化性脑血管和脑组织 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， 2)低度阿尔茨海默病病理；3)中度/高度阿尔茨海默病病理 。这些 大脑 捐助者在#年期间完成了国家阿尔茨海默氏症协调中心统一数据集年度评估 并且有可用的基于共识的认知诊断。该提案旨在利用现有的 资源来进行新的发现。脑血管和脑组织的配对和平行研究将 为脑血管重塑和AD的时间发展提供新的认识。理解 血管重塑在阿尔茨海默病中的作用可能导致发现新的治疗方案和 预防阿尔茨海默病的干预措施说明。

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.