Syntaxin17介导的自噬体-溶酶体融合信号轴在甲基苯丙胺引起阿尔兹海默样病理性蛋白积聚中的作用及机制

甲基苯丙胺（Meth）滥用已成为危害人类健康的重大公共卫生问题。除急性损伤外，近期研究显示，Meth滥用会导致脑衰老、神经退行性等渐进性脑损伤，但机制不明。课题组前期结果显示，Meth暴露可引起阿尔兹海默病（AD）样改变，其病理性蛋白Aβ，p-tau等上调。亦发现，Meth阻碍自噬体-溶酶体融合，该过程中关键调节蛋白Syntaxin17、SNAP29及VAMP8显著下调。基于溶酶体对Aβ，p-tau等蛋白清除的关键性，我们认为：Syntaxin17-SNAP29-VAMP8信号轴紊乱致Meth引起自噬-溶酶体的融合障碍可能是AD样改变的重要原因。为此，该项目拟借助海马区Syntaxin17、SNAP29、VAMP8高表达的小鼠模型及原代海马神经元高表达的细胞模型，结合行为学、电生理、分子生物学等方法，系统阐述Meth暴露引起AD样改变的潜在机制，继而提供可能的治疗靶点和干预策略。

The new type drug abusing, mostly referred to as methamphetamine (Meth), has become a serious public health problem worldwide. Besides the acute brain injury, Meth chronic abusing leads to progressive brain damage, such as brain aging, neurodegenerative disease, etc. However, the potential mechanism is unknown. Our previous work found that Meth exposure contributed to Alzheimer's disease (AD) like changes, which manifested as the elevation of the Aβ and p-tau expression. Intriguingly, the dysfunction of autophagy-lysosome fusion was observed after the Meth treatment. Noteworthily, Syntaxin17，SNAP29 and VAMP8, which were demonstrated to be closely associated with the autophagy-lysosome fusion, were obviously decreased after administration of Meth. Based on the importance of the lysosome on Aβ and p-tau clearance, we hypothesized that the disturbance of the Syntaxin17-SNAP29-VAMP8 signaling axis mediated by Meth might resulted in the dysfunction of autophagy-lysosome fusion, and finalized the accumulation of AD like pathological protein. Therefore, in the present work, the Syntaxin17, SNAP29, VAMP8 high expression in hippocampus mouse model and the high expression primary hippocampal neuron model were used, with the aim to fully elucidate the mechanisms involving the roles Syntaxin17-SNAP29- VAMP8 signaling axis in the accumulation of the AD like pathological proteins through the assays of the behavior, electrophysiology and molecular biology. These studies, taken together, might provide the newly insights into the early interventional strategies for Meth-mediated AD like neural degenerative diseases.