TYROSINE PHOSPHORYLATION IN ALZHEIMERS DISEASE

阿尔茨海默病中的酪氨酸磷酸化

• 批准号: 6372450
• 负责人: Gloria Lee
• 金额: $ 25.78万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-05-01 至 2004-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6372450
• 关键词: Agnatha; Alzheimer's disease; biological signal transduction; cell differentiation; disease /disorder model; human tissue; immunocytochemistry; immunoelectron microscopy; laboratory mouse; monoclonal antibody; neurofibrillary tangles; paired helical filament; phosphorylation; protein isoforms; protein localization; protein structure function; protein tyrosine kinase; tau proteins; tissue /cell culture; western blottings

DESCRIPTION (from Applicant's abstract) Neurofibrillary tangles are a major pathological hallmark of Alzheimer's disease (AD). These tangles contain abnormal paired helical filaments (PHF), whose primary component is tau. Tau is a neuronal microtubule associated protein that is essential for the development and maintenance of axons. Tau in tangles is abnormally phosphorylated on serines and threonines but the significance of these phosphorylations and the pathways leading to tangle formation remain unknown. The applicant now finds that tau associates with src family non-receptor tyrosine kinases, including fyn, and that tau is tyrosine phosphorylated in human neuroblastoma cells. Moreover, they find that anti-phosphotyrosine antibodies react with PHF-tau from AD brain and that anti- phosphotyrosine staining co-localizes with the anti-PHF staining of neurofibrillary lesions in AD brain. Consistent with these results, other studies find that fyn is up-regulated in AD and that an increase in tyrosine phosphorylation follows exposure of neuronal cells to A-beta peptide. Based on her findings, other studies, and the key role played by tyrosine phosphorylation in signal transduction during growth and development, the applicant hypothesizes that tyrosine phosphorylation of tau plays a critical role in neurofibrillary tangle formation in Alzheimer's disease. Here it is proposed to determine the impact of tyrosine phosphorylation on the function of tau and to assess the role of tyrosine phosphorylation of tau in tangle formation. In Aim I, they will identify the tyrosine in tau that is phosphorylated and determine how tyrosine phosphorylation affects the function of tau. In Aim II, they will further characterize the tyrosine phosphorylation of tau in AD brain and in their lamprey model for human tau filament assembly in situ. In Aim III, they will determine the expression of tyrosine phosphorylation of tau during neuronal differentiation, brain development, aging and disease. These studies will help determine the role of tyrosine phosphorylation of tau in PHF assembly and may aid in the development of mouse models of AD. Moreover, since the A-beta peptide increases tyrosine phosphorylation in neuronal cells, tyrosine phosphorylation may be the link between amyloid plaque formation and neurofibrillary tangles. Insights into the tyrosine phosphorylation of tau may provide an important step forward in elucidating the pathways leading to neurofibrillary tangle formation in AD.

描述（来自申请人摘要） 神经元缠结是阿尔茨海默氏症的主要病理标志 疾病（AD）。这些缠结包含异常的成对螺旋丝 (PHF)，其主要成分是τ。Tau是神经元微管 相关蛋白质，对于发育和维持 的轴突。缠结中的Tau在丝氨酸上异常磷酸化， 但这些磷酸化的意义和 导致缠结形成的途径仍然未知。申请人目前 发现tau与src家族非受体酪氨酸激酶相关， 包括Fyn，并且tau在人类中是酪氨酸磷酸化的， 神经母细胞瘤细胞此外，他们发现抗磷酸酪氨酸 抗体与来自AD脑的PHF-tau反应， 磷酸酪氨酸染色与抗PHF染色共定位， AD脑内的神经系统病变。与这些结果一致， 其他研究发现fyn在AD中上调， 在神经元细胞暴露于A-β之后的酪氨酸磷酸化中 肽。根据她的发现，其他研究，以及在 通过生长过程中信号转导中的酪氨酸磷酸化， 发展，申请人假设酪氨酸磷酸化 tau蛋白在神经元缠结的形成中起着关键作用， 老年痴呆症 在这里，它建议确定酪氨酸磷酸化的影响， 对tau蛋白功能的影响，并评估酪氨酸 缠结形成中tau的磷酸化。在目标I中，他们将确定 tau蛋白中的酪氨酸被磷酸化，并决定酪氨酸 磷酸化影响tau的功能。在Aim II中，他们将 进一步表征AD脑中tau的酪氨酸磷酸化， 在他们的七鳃鳗模型中，人类tau蛋白丝在原位组装。在Aim中 III，它们将决定酪氨酸磷酸化的表达， tau蛋白在神经元分化、脑发育、衰老和 疾病这些研究将有助于确定酪氨酸的作用 在PHF装配中tau的磷酸化，并可能有助于发展 AD的小鼠模型。此外，由于A-β肽增加 在神经元细胞中，酪氨酸磷酸化可以 是淀粉样蛋白斑形成和神经胶质瘤之间的联系 缠结。深入了解tau蛋白的酪氨酸磷酸化可能会提供 在阐明导致 AD的神经元缠结形成。