Drug Discovery of Alzheimer Disease from Molecules- Regulating Microtubule Polymerization

基于阿尔茨海默病是由微管聚合缺陷引起的假设，我们研究了新发现的微管调节分子Pin1和Gas7b(其序列与Pin1的WW结构域相似)的功能。提示Pin1和Gas7b对年龄相关性疾病的诊断和治疗有一定的参考价值。我们成功地建立了PIN1低分子抑制剂的高通量筛选技术，鉴定了DTM、TME-1和海藻多酚(974B)。我们发现，Gas7b通过结合磷酸化tau来加速微管聚合，通过调节微管的捆绑和微管与肌动蛋白细丝的交联来调节神经细胞的形态，在阿尔茨海默病患者的大脑中存在较低的水平。(原文；41份)

Based on the hypothesis that Alzheimer disease is caused by the defect of microtubule polymerization, we have studied the functions of the newly identified the microtubule- regulatory molecules, Pin1 and Gas7b (the proteins consisting of the similar sequence to the WW domain of Pin1). We suggested that Pin1 and Gas7b are useful to the diagnosis and treatment of the age-related diseases. We succeeded in establishing the high throughput screening technology for the low molecular inhibitors of Pin1 and identifying DTM, TME-1 and seaweed polyphenol (974B). We showed that Gas7b accelerates microtubule polymerization by binding phosphorylated tau, regulates neuronal cell morphology by regulating the bundling of microtubules and cross linking of microtubule and actin filament, and exists less level in the brains of patients with Alzheimer disease. (original papers; 41)