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

Tau 诱导的内皮细胞损伤是阿尔茨海默病微血管功能障碍的驱动因素

• 批准号: 10295028
• 负责人: Andy Banh
• 金额: $ 3.29万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-15 至 2022-08-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10295028
• 关键词: Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Antibody Therapy; Binding; Biological Markers; Biology; Blood Vessels; Blood flow; Brain; Cardiovascular Diseases; Cell Aging; Cell surface; Cells; Cerebrovascular Circulation; Cerebrovascular Disorders; Cerebrovascular system; Cytoskeleton; Data; Dementia; Deterioration; Development; Diagnosis; Disease; Disease Progression; Elements; Endothelial Cells; Endothelium; Enzymes; Etiology; Exposure to; Functional disorder; Heparan Sulfate Proteoglycan; Human; Impairment; In Vitro; Individual; Inflammatory; Intercellular Fluid; Knock-out; Knowledge; Laboratories; Lead; Literature; Measures; Mediating; Membrane; Microtubule Stabilization; Microtubules; Microvascular Dysfunction; Molecular; Mus; NOS3 gene; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Pathogenicity; Pathologic; Pathology; Pathway interactions; Patients; Phenotype; Play; Preparation; Principal Investigator; Process; Public Health; Publishing; Regulation; Research; Role; Scientist; Senile Plaques; Specificity; Tauopathies; Techniques; Testing; Therapeutic Intervention; Training Activity; Vascular blood supply; Vasodilation; base; brain endothelial cell; career; cerebrovascular; cerebrovascular health; cerebrovascular pathology; endothelial dysfunction; extracellular; in vivo; insight; middle age; mouse model; novel; protein aggregation; senescence; skills; tau Proteins; tau aggregation; tau phosphorylation; therapeutic development; transmission process; uptake

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.

项目总结/摘要 阿尔茨海默氏病是一种进行性神经退行性疾病，导致显著的个体痛苦， 一个重大的公共卫生负担。阿尔茨海默病的病理生理学不清楚， 有效的疾病修饰疗法的发展，因此，目前没有治疗性的药物。 阻止或逆转疾病进程的干预措施。越来越清楚的是，脑血管功能障碍和 心血管疾病是神经变性和痴呆的主要原因。脑血管功能障碍 是阿尔茨海默病中发生的第一个也是最重要的异常，可能与其他疾病相互作用。 病理因素来驱动阿尔茨海默病的病理进展。两种标志性的病理 阿尔茨海默病的主要病因是细胞外的β-淀粉样蛋白斑块和细胞内的神经纤维缠结， Tau蛋白初步研究表明，可传播的可溶性tau聚集体，一种tau， 涉及tau病理学和神经变性的传播，在脑血管内皮细胞中积累， 在几种tau蛋白病小鼠模型和诊断患有阿尔茨海默病的人类患者中， 或其他tau蛋白病。暴露于可溶性tau聚集体导致体外内皮细胞功能障碍。 此外，tau蛋白病的小鼠模型在中年时显示内皮功能受损。的机制 其中可溶性tau聚集体被传递到内皮细胞，以及它们在内皮细胞的发展中的作用。 然而，脑血管功能障碍尚不清楚。已发表的文献表明，可溶性tau聚集体 通过结合细胞表面硫酸乙酰肝素蛋白聚糖（HSPG）从神经元到神经元。根据这些发现， 所提出的研究将检验可溶性tau蛋白聚集体传递到微血管内皮细胞的假设， 细胞中的HSPG通过tau蛋白与细胞表面HSPG的结合来介导，并在体外和体内驱动内皮功能障碍。目的 1将确定tau蛋白与细胞表面HSPG结合在可溶性tau蛋白聚集体进入内皮细胞中的作用 和体外内皮细胞功能障碍的发展。目的2将确定可溶性tau蛋白的作用 在tau蛋白病小鼠模型中，通过去除可溶性聚集物， 使用抗体处理从脑中聚集tau。这些研究将利用详细的特异性 的体外技术和体内方法的可翻译性，以表征一种新的元素， 脑血管病理学和阿尔茨海默病病理生理学。完成拟议的研究将 提供关于阿尔茨海默病病因决定因素的重要知识。这方面的知识可以 用于开发针对脑血管功能障碍的治疗干预措施， 发生在老年痴呆症中。完成拟议的研究和 该应用程序也将准备作为一个独立的临床科学家的职业生涯的主要研究者。