CDK5/JIP3途径参与阿尔茨海默病的溶酶体转运调控

在抗淀粉样蛋白药物和Tau蛋白药物治疗阿尔茨海默病（AD）陆续受挫后，人们开始转变研发方向。溶酶体转运障碍是AD重要病理改变之一，备受瞩目，但其病理机制仍不清。有研究发现JNK相互作用蛋白3(JIP3)参与溶酶体转运，我们的预实验发现JIP3是CDK5新磷酸化底物。为此我们提出假说，CDK5通过磷酸化JIP3来介导溶酶体转运参与AD病理过程。为验证这一假说，我们将通过CDK5和JIP3的生化特性、N2a/APP695和5xFAD的细胞模型和6种转基因小鼠（jip3 condition KO、jip3-S586A、jip3-S586E、5xFAD、p35KO和p25KI基因小鼠）为动物模型，从体外、细胞、组织和动物水平探讨CDK5调控JIP3及活化的JIP3调节溶酶体运输来影响AD的认知功能。本研究将从CDK5-JIP3这个新视点来揭示AD的发病机制，为其治疗提供新思路。

Going through failures of β-amyloid-targeted and tau-targeted agents for the treatment of Alzheimer disease forces scientists turn to new direction. In addition, dysfunction of lysosomal transport, one of important pathophysiological events of AD, is getting more and more attention. However, the detailed pathological mechanism of lysosomal axoplasmic transport still remains unclear. It has been reported that JNK-interacting protein 3 (JIP3) is a vital role in regulation of lysosomal transport in AD. On the other hand, from the amino acid sequence assay, it has been found that JIP3 is an optimal substrate for CDK5. But little has been known about CDK5 on JIP3 in its pathological transport in AD. Based on our preliminary results, JIP3 has been proved to be a new substrate for CDK5. Thus, we hypothesize that the JIP3 regulated by CDK5 is involved in the axoplasmic transport of synaptic lysosomes in the process of AD. In order to assess our hypothesis, 1) the interaction of JIP3 and CDK5 and the phosphorylation of JIP3 by CDK5 will be examined by in vivo biochemical assays, 2) the pathophysiological functions of JIP3 and CDK5 will be evaluated in cultured N2a/APP695 and primary cortical/ hippocampal neurons, and AD models of six types of genetically engineered mice including jip3 condition KO, jip3-S586A, jip3-S586E, 5xFAD, p35KO and p25KI. In a word, it is the first time that we find a novel pathway, in which JIP3 as a new substrate phosphorylated by CDK5 probably underlies synaptic dysfunction caused by lysosomal axoplasmic transport defect. Deciphering this pathway will be potentially beneficial for AD therapy.