THE MICROTUBULE PROTEIN TAU IN ALZHEIMER'S DISEASE

以前，我们已经证明，一个异常磷酸化的 作为微管相关蛋白的一种形式，tau与 与成对螺旋丝相关，并在 老年痴呆症大脑 利用我们的基础生物学知识， 蛋白质，我们建议比较生物化学和细胞生物学 阿尔茨海默病患者大脑中的可溶性tau蛋白与非痴呆患者大脑中的可溶性tau蛋白相比， 控制大脑 为了确定是否与疾病相关的改变 影响tau的所谓的“正常”功能，从 阿尔茨海默氏症和对照组的大脑将被测定其在以下方面的功效： 刺激体外微管组装。 此外，与两个 现有的针对tau的单克隆抗体，一种不结合 异常磷酸化的形式和一个结合到所有 这种蛋白质的形式，我们建议：1）确定量的 老年痴呆症与非痴呆症大脑中的可溶性tau蛋白，2） 含tau蛋白的老年斑和神经胶质瘤的数量 通过免疫组织化学测定的缠结， 组织提取物中的可溶性tau，3）测定组织提取物中tau的量， 阿尔茨海默病患者与非阿尔茨海默病患者的CSF和血清形式 痴呆对照人群，4）确定 脑组织提取物中的磷酸化/非磷酸化tau， 与对照样品相比，阿尔茨海默病的血清和CSF，以及5）提供 将这些数据提交给核心， 确定痴呆的程度。 此外，新的单克隆 将产生与阿尔茨海默病tau蛋白结合但不与 以获得靶向磷酸化的探针 和其他可能的变化，这种蛋白质的一部分， 老年痴呆症病理学

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.