TYROSINE PHOSPHORYLATION IN ALZHEIMERS DISEASE

描述(摘自申请人的摘要) 神经原纤维缠结是阿尔茨海默氏症的主要病理特征 疾病(AD)。这些缠结包含异常的成对螺旋细丝。 (PHF)，其主要成分为tau。Tau是一种神经元微管。 在发育和维持过程中必不可少的相关蛋白质 轴突。缠结中的tau在丝氨酸上异常磷酸化， 苏氨酸，但这些磷酸化的意义和 导致缠结形成的途径仍不清楚。申请人现在 发现tau与src家族非受体酪氨酸激酶有关， 包括fyn，而且tau在人类体内是酪氨酸磷酸化的。 神经母细胞瘤细胞。此外，他们还发现，抗磷酸酪氨酸 抗体与AD脑中的PHF-tau反应，抗- 磷酸酪氨酸染色与抗PHF染色共定位 阿尔茨海默病脑内神经纤维性病变。与这些结果一致， 其他研究发现，Fyn在AD中上调，而且增加 在神经细胞暴露于A-β后酪氨酸磷酸化 多肽。根据她的发现，其他研究以及所扮演的关键角色 通过酪氨酸磷酸化在生长和发育过程中的信号转导 发展，申请人假设酪氨酸磷酸化 Tau在神经纤维缠结形成中起关键作用 阿尔茨海默氏症。 在这里，建议确定酪氨酸磷酸化的影响 论tau的功能及酪氨酸的作用 缠结形成过程中tau的磷酸化。在AIM I中，他们将确定 Tau中的酪氨酸被磷酸化，并决定酪氨酸如何 磷酸化影响tau的功能。在AIM II中，他们将 AD脑内tau蛋白酪氨酸磷酸化的进一步研究 在他们的七鳃鳗模型中进行人tau丝的原位组装。在AIM III，他们将测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 PHF组装中tau的磷酸化，并可能有助于发育 阿尔茨海默病的小鼠模型。此外，由于A-β多肽增加 神经细胞中的酪氨酸磷酸化，酪氨酸磷酸化可能 是淀粉样斑块形成和神经纤维之间的纽带 唐格斯。对tau酪氨酸磷酸化的洞察可能会提供 在阐明通向 阿尔茨海默病的神经原纤维缠结形成。

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.