CIP2A对蛋白磷酸酯酶2A的调节及其在阿尔茨海默病发病中的作用

The activity of protein phosphatase 2A (PP2A) is decreased in AD brain, which participates in the formation of NFTs and amyloid plaques, but the upstream factors that inducing PP2A inhibition remain largely unclarified. Recent studies imply that one newly discovered protein CIP2A is up-regulated in numerous peripheral tumors and specifically inhibits c-Myc associated PP2A. Whether or not CIP2A also plays a role in brain PP2A regulation and AD development is elusive. Our preliminary data show that CIP2A is up-regulated in the brain of AD animal models. In neuronal cells, CIP2A shares the same cytoplasmic localization with PP2A, over-expression of CIP2A results in PP2A inhibition and AD-like tauopathy. Based on these finding, we will use biochemical and molecular strategies in AD human brain tissue, cell and animal models: 1) to examine the expression, distribution and co-localization of CIP2A and PP2A in AD/control human and transgenic mice brains, and analyze the relationship of CIP2A with PP2A activity and AD-like pathologic changes; 2) to explore the substrate-specificity of CIP2A on PP2A regulation, especially on PP2A dephosphorylation on tau/APP, two proteins directly associated with AD hallmarks; 3) to explore whether or not CIP2A up-regulation may induce PP2A inhibition and AD pathological changes in cultured primary neurons through overexpressing CIP2A plasmid; 4) to explore whether or not down-regulation of CIP2A through SiRNA interfering or blokade of the interaction of CIP2A with tau/APP may prevent the development of AD pathological changes in AD cell and animal models, and evaluate the potential value of CIP2A as a drug target. Studies from this project will disclose the new function of the cancerous protein CIP2A in the brain and in the development of AD, thus provide absolutely new clues for the mechanism of PP2A dysregulation and valuable information for the design of potential neuroprotective strategies of AD.

蛋白磷酸酯酶2A（PP2A）活性在AD脑中下降并参与AD特征病变形成，其机制不明。最新研究发现在多种肿瘤细胞中一种CIP2A蛋白表达增高并特异抑制c-Myc相关PP2A活性。关于脑中CIP2A对PP2A的调节在AD发病中的作用尚无报导。项目前期研究发现CIP2A在AD动物脑内上调,在神经细胞内与PP2A共定位于胞浆,其过表达可抑制PP2A并导致AD样tau病变。本项目拟从AD患者/转基因动物，培养神经元和分子水平系统研究AD脑中CIP2A与PP2A活性和AD样病变相关性;明确其对PP2A调节的底物特异性，特别是对AD特征病变相关蛋白tau/APP的磷酸化调节特异性;在神经元内上调CIP2A表达，探讨其是否导致PP2A活性下降和AD样病变；在AD模型下调CIP2A表达或干预其和tau/APP结合，明确其对AD相关病变的治疗作用。研究将阐明脑内PP2A活性调节新途径，为AD防治提供新靶点。

蛋白磷酸酯酶2A（PP2A）活性在AD 脑中下降并参与AD 特征病变形成，其机制不明。最新研究发现在多种肿瘤细胞中一种CIP2A 蛋白表达增高并特异抑制c-Myc 相关PP2A 活性。关于脑中CIP2A 对PP2A 的调节在AD 发病中的作用尚无报导。在本项目中，我们系统探讨了CIP2A在AD发病中的作用和机制。研究发现在AD脑中CIP2A上调，CIP2A上调可导致tau/APP磷酸化，增加APP的β剪切和Aβ的产生。CIP2A过表达同时也导致tau蛋白异位分布于树突和树突棘，进而引起突触退变。在小鼠脑中通过脑内注射AAV-CIP2A导致CIP2A过表达可引起AD样认知功能障碍，LTP受损以及AD样病变。此外，Aβ可导致神经元内CIP2A表达增加，形成恶性循环。我们的研究阐明了脑内PP2A 活性调节新途径，为AD 防治提供了新的靶点。