THE MICROTUBULE PROTEIN TAU IN ALZHEIMER'S DISEASE

之前，我们已经证明了一种异常的磷酸化 作为微管相关蛋白的一种，tau与 与成对螺旋细丝相关，并在 阿尔茨海默病的大脑。利用我们对这一现象的基本生物学知识 蛋白质，我们建议将生物化学和细胞生物学 阿尔茨海默病患者与非痴呆者脑组织中可溶性tau的比较 控制大脑。以确定疾病相关的改变是否 影响tau所谓的“正常”功能，从 阿尔茨海默病和对照组的大脑将在 体外刺激微管组装。此外，有两个 现有的抗tau的单抗，一种不与 一种异常的磷酸化形式，与所有的 这种蛋白质的形式，我们建议：1)确定 阿尔茨海默病患者与非痴呆者大脑中的可溶性tau，2)与 含tau的老年斑和神经原纤维的数量 用免疫组织化学方法测定的缠结蛋白 组织提取物中的可溶性tau，3)测定组织提取物中tau的含量 阿尔茨海默病患者与非阿尔茨海默病患者的脑脊液和血清 痴呆症控制人群，4)确定 脑组织提取物中的磷酸化/非磷酸化tau， 阿尔茨海默病患者的血清和脑脊液与对照样本，以及5)供应 这些数据到核心进行关联，以进行诊断 确定痴呆症的程度。此外，新的单抗 会产生与阿尔茨海默病tau结合的抗体，但不会 为了获得靶向磷酸化的探针 以及该蛋白质中其他可能的变化作为 阿尔茨海默病病理学。

Previously, we have shown that an abnormally phosphorylated form of the microtubule-associated protein, tau is intimately associated with paired-helical filaments and is overexpressed in Alzheimer brain. Using our knowledge of the basic biology of this protein, we propose to compare the biochemistry and cell biology of soluble tau from Alzheimer brain with that from non-demented control brain. To determine whether disease related alterations affect tau's purported "normal" function, purified tau from Alzheimer and control brains will be assayed for its efficacy in stimulating microtubule assembly in vitro. Furthermore, with two existing monoclonal antibodies to tau, one which does not bind to the abnormally phosphorylated form and one which binds to all forms of this protein, we propose to: 1) determine the amounts of soluble tau in Alzheimer vs. non-demented brains, 2) correlate the number of tau-containing senile plaques and neurofibrillary tangles as determined by immunohistochemistry with the levels of soluble tau in tissue extracts, 3) determine the amount of tau in CSF and serum form patients with Alzheimer disease vs. non- demented control populations, 4) determine the ratio of phosphorylated/nonphosphorylated tau in brain tissue extracts, sera and CSF of Alzheimer vs. control samples, and 5) to supply these data to the Core for correlation with diagnostically determined degrees of dementia. In addition, novel monoclonal antibodies will be raised which bind to Alzheimer tau but not to normal tau in order to obtain probes which target phosphorylation and other possible alterations in this protein as a part of Alzheimer pathology.