Tau-induced endothelial cell impairment as a driver of microvascular dysfunction in Alzheimer's disease

项目摘要/摘要 阿尔茨海默病是一种进行性神经退行性疾病，会导致严重的个人痛苦和 这是一个主要的公共卫生负担。阿尔茨海默病的病理生理学解释很差，限制了 开发有效的疾病修正疗法，因此，目前还没有治疗方法 阻止或逆转疾病进程的干预措施。越来越明显的是，脑血管功能障碍和 心血管疾病是导致神经变性和痴呆症的主要因素。脑血管功能障碍 是阿尔茨海默病中发生的第一个也是最显著的异常，可能与其他 推动阿尔茨海默病病理进展的病理因素。两种标志性的病理学 阿尔茨海默病的特征是细胞外的β-淀粉样斑块和细胞内的神经原纤维缠结 Tau蛋白。初步研究表明，可传递的可溶性tau聚集体，即tau的一种 牵涉到tau病理的扩散和神经变性，积聚在脑血管内皮细胞 细胞在体外，在几种肌萎缩侧索硬化症小鼠模型中，以及在诊断为阿尔茨海默病的人类患者中 或其他变态疗法。暴露在可溶性tau聚集体中会导致体外培养的内皮细胞功能障碍。 此外，自闭症的小鼠模型显示中年时血管内皮功能受损。这个机制是通过 哪些可溶性tau聚集体被传递给内皮细胞及其在血管内皮细胞生长发育中的作用 然而，脑血管功能障碍尚不清楚。已发表的文献表明，可溶的tau聚集体广泛存在 通过结合细胞表面硫酸乙酰肝素蛋白多糖(HSPG)从神经元到神经元。基于这些发现， 拟议的研究将检验可溶tau聚集传递到微血管内皮细胞的假设。 细胞是通过tau与细胞表面HSPG结合而介导的，并在体外和体内驱动内皮细胞功能障碍。目标 1将确定tau与细胞表面hspg结合在可溶性tau聚集体进入内皮细胞中的作用。 以及血管内皮细胞功能障碍在体外的发展。目标2将确定可溶性tau的作用 去除可溶性的聚集物在血管内皮细胞功能障碍小鼠模型中的发展 使用抗体治疗，tau从大脑聚集。这些研究将利用详细的特殊性 体外技术和体内方法的可译性来表征一种新的元素 脑血管病理学和阿尔茨海默病的病理生理学。完成建议的研究后， 提供有关阿尔茨海默病病因决定因素的重要知识。这一知识可以是 用于开发针对脑血管功能障碍的治疗干预措施，这是第一种异常 这发生在阿尔茨海默氏症中。完成建议的研究及详述的培训活动 这一申请还将使首席研究员为成为一名独立的临床科学家做好准备。

Project Summary/Abstract Alzheimer’s disease is a progressive neurodegenerative disorder that causes significant individual suffering and a major public health burden. The poorly elucidated pathophysiology of Alzheimer’s disease limits the development of effective disease modifying therapy and, as a result, there are currently no therapeutic interventions that halt or reverse the disease process. It is becoming clear that cerebrovascular dysfunction and cardiovascular disease are major contributors to neurodegeneration and dementia. Cerebrovascular dysfunction is the first and most significant abnormality that occurs in Alzheimer’s disease and may interact with other pathological factors to drive the pathological progression of Alzheimer’s disease. The two hallmark pathologies of Alzheimer’s disease are the extracellular β-amyloid plaques and intracellular neurofibrillary tangles composed of tau protein. Preliminary studies show that transmissible soluble tau aggregates, a species of tau that is implicated in the spread of tau pathology and neurodegeneration, accumulate in cerebrovascular endothelial cells in vitro, in several mouse models of tauopathy, and in human patients diagnosed with Alzheimer’s disease or other tauopathies. Exposure to soluble tau aggregates causes endothelial cell dysfunction in vitro. Furthermore, mouse models of tauopathy show impaired endothelial function by middle age. The mechanism by which soluble tau aggregates are transmitted to endothelial cells and their role in the development of cerebrovascular dysfunction, however, are unclear. Published literature show that soluble tau aggregates spread from neuron to neuron by binding cell surface heparan sulfate proteoglycans (HSPG). Based on these findings, the proposed studies will test the hypothesis that soluble tau aggregate transmission to microvascular endothelial cells is mediated by tau binding to cell surface HSPG and drives endothelial dysfunction in vitro and in vivo. Aim 1 will determine the role of tau binding to cell surface HSPG in soluble tau aggregate entry into endothelial cells and the development of endothelial cell dysfunction in vitro. Aim 2 will determine the role of soluble tau aggregates in the development of endothelial dysfunction in a mouse model of tauopathy by removing soluble tau aggregates from the brain using antibody treatment. These studies will make use of the detailed specificity of in vitro techniques and the translatability of in vivo approaches to characterize a novel element of cerebrovascular pathology and Alzheimer’s disease pathophysiology. Completion of the studies proposed will provide crucial knowledge about the etiological determinants of Alzheimer’s disease. This knowledge can be used in the development of therapeutic interventions that target cerebrovascular dysfunction, the first abnormality that occurs in Alzheimer’s disease. The completion of the studies proposed and the training activities detailed in this application will also prepare the principal investigator for a career as an independent clinician scientist.