申请者叶克强和国内合作者王建枝在阿尔茨海默病（AD）研究方面有丰富的积累，分别在国际高影响力杂志发表系列论文并被国际同行广泛引用。最近关于tau蛋白被天冬酰胺酰内肽酶（AEP）切割及tau蛋白SUMO化修饰毒性作用的合作研究结果分别在Nat Med和PNAS发表。本项目拟在前期合作研究基础上，进一步探讨AEP切割产生的tau1-368和淀粉样前体蛋白毒性片段（APP1-373 或APP586-695）是否在小鼠脑中导致神经原纤维缠结和老年斑的形成？AEP切割产生的tau和APP毒性片段对AD样病变是否相互促进？研究结果将揭示AD的新致病因素，为阐述AD发病机制提供新思路，并有望获得模拟AD样神经原纤维缠结的动物模型。

The applicant (Keqiang Ye) and the domestic collaborator (Jianzhi Wang) have been working on Alzheimer’s disease (AD) for many years. They have published over hundred research papers in peer-reviewed high-impact international journal. Recently, two of their collaborative papers have been published respectively in Nat Med and PNAS, one paper describes cleavage of tau proteins by asparagine endopeptidase (AEP) and its potential pathological role in AD neurodegeneration and memory impairments, and another one demonstrates the toxic effects of tau SUMOylation. Based on the findings of AEP, the current project will further study whether the cleaved neuronal toxic tau1-368 and amyloid precursor protein (APP1-373 or APP586-695) can induce formation of neurofibrillary tangles plaques in the mice? Whether the pathological effects of the toxic tau and APP fragments are synergistic? By answering these questions, we will reveal new etiological factors and provide new animal model for AD drug research and development.

年龄依赖性的天冬酰胺内肽酶—δ-分泌酶，能够切割淀粉样前体蛋白APP和微管相关蛋白tau。APP和tau是阿尔茨海默病中形成老年斑和神经原纤维缠结所必需的。然而，δ-分泌酶的激活是否可以触发AD样病理学变化和行为学异常目前尚不清楚。在本项目中，我们发现，在C57小鼠脑内过表达δ-分泌酶切割所产生的tau1-368片段或淀粉样前体蛋白毒性片段（APP586-695），可诱导AD样病理学改变和行为学障碍。在共表达APP的情况下，tau1-368可导致BACE1强表达及Abeta的产生。与全长tau片段相比，tau1-368片段可结合更多的磷酸化STAT1（激活STAT1），而STAT1已知是BACE1的转录因子，tau1-368片段可促使STAT1核转位，从而上调BACE1的表达，导致Abeta产生。更为重要的是，Aβ可激活激酶SGK1或JAK2，从而磷酸化STAT1，诱导其与tau1-368的结合。抑制SGK1或JAK2可逆转Tau1-368对BACE1的激活效应。下调STAT1可逆转tau1-368和APP586-695过表达所诱导的AD样病理学改变和行为学异常。因此，本项目研究结果表明，中tau不仅仅是Aβ假说中Aβ的下游，它还可被δ-分泌酶切割后促使Aβ的生成。