Aβ-PirB-Tau通路调控突触可塑性：阿尔茨海默症发生的分子机制及防治策略探讨

项目名称： Aβ-PirB-Tau通路调控突触可塑性：阿尔茨海默症发生的分子机制及防治策略探讨

项目编号： No.81471415

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 苟兴春

作者单位： 西安医学院

项目金额： 70万元

中文摘要： 神经元突触可塑性下降或突触丢失是引起阿尔茨海默症（AD）发生发展的主要原因之一。最新研究发现，PirB是可溶性低聚物Aβ的受体，可能通过受体胞内信号调节突触可塑性，但具体机制并不清楚。前期预实验显示PirB在AD模型中高表达；阻断PirB后，PP-2A、PP-2B活性上调，GSK3β下调。因此，我们推测PirB参与AD发生按如下过程进行：低聚Aβ与PirB结合；通过促进磷酸激酶活性或者/和抑制磷酸酯酶的活性；促进Tau蛋白异常磷酸化即过度磷酸化；破坏神经元轴突微管的形成和维持；导致突触丢失和突触可塑性下降、从而引起AD发生。因此，我们拟证实Aβ-PirB-Tau信号通路是AD发生发展的一种重要机制之一；同时拟利用PirB受体的胞外段（PirBex）竞争性抑制Aβ与内源性PirB受体结合(即阻断Aβ-PirB通路)，促进AD模型动物认知功能改善，为有效地预防及治疗AD提供新的途径。

中文关键词： 阿尔茨海默病；突触可塑性；β淀粉样蛋白；tau蛋白磷酸化；认知障碍

英文摘要： Synaptic plasticity decrease or loss of synapses is one of the main causes of Alzheimer's disease (AD). Latest researches have demonstrated that PirB is a receptor of soluble Aβ oligomer and further regulate synaptic plasticity through intracellular signaling pathways, but the exact mechanism is still unclear. Here, we hypothesized that PirB might play an important role in the development of AD and the possible pathogenetic mechanisms are as follows: After the combination of oligomeric Aβ with PirB, PirB enhanced the abnormal phosphorylation (hyperphosphorylation) of Tau protein by promoting phosphatase activity or/and inhibiting phosphokinase (PP-2A, PP-2B) activity, which could undermine the formation and maintenance of neuronal axonal microtubules and resulted in the loss of synapses and declination of synaptic plasticity and finally leading to the occurrence of AD diseases. Therefore, we proposed a hypothesis that Aβ-PirB-Tau signaling pathway might be an important mechanism of AD pathogenesis. In this study, the extracellular domain of PirB (PirBex) was used to competitively inhibit the combination of Aβ and endogenous PirB receptor (blockage of Aβ-PirB pathway), thereby reducing the abnormal phosphorylation of Tau to promote the improvement of cognitive function of AD animal model. Our research will not only provide new insight into the mechanism of AD development but also present a new method to prevent and treat AD.

英文关键词： AD;Synaptic plasticity;Aβ;Tau phosphorylation;cognitive disorder