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Pathogenesis of Alzheimer's disease by aberrant APP transport

APP 转运异常导致阿尔茨海默病的发病机制

基本信息

批准号：
20390018
负责人：
SUZUKI Toshiharu
金额：
$ 12.48万
依托单位：
Hokkaido University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2008
资助国家：
日本
起止时间：
2008 至 2010
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-20390018/
关键词：
アルツハイマー病 APP 小胞輸送キネシン神経神経変性疾患 βアミロイドアミロイド前駆体タンパク質キネシンモーター膜小胞輸送微小管タンパク質リン酸化神経細胞軸索順行輸送老化アルカデイン JIP セクレターゼ

项目摘要

Major cause of Alzheimer's disease is production of β-amyloid (Aβ) and neurotoxic oligomer formation of Aβ. Aβ is a metabolic product generated by cleavage of the amyloid β-protein precursor (APP) by the successive action of β- and γ-secretases. Mutation in the presenilin component of γ-secretase can cause alternative intramembrane processing of APP, leading to aberrant speciation of Aβ, which, in turn, can lead to familial AD (FAD). In contrast to FAD, the primary cause of sporadic type of AD remains unclear. Several membrane and trnasmembrane proteins have been associated with AD, and the disruption of the vesicular transport system is observed in AD brains, suggesting that defects in the membrane trafficking system, including axonal vesicular transport, may be a primitive cause of AD pathogenesis. I focused this research on the analysis of APP vesicular trafficking. APP is known to cargo-receptor of kinesin-1. Our previous studies revealed that APP is associated to KLC through JIP1 mediation. Furthermore, disruption of APP vesicular transprort increased the generation of neurotoxic Aβ. However, the molecular mechanism how APP and kinesin-1 association is regulated remains unclear in detail. We revealed the association between JIP1 and KLC in detail and proposed how the association is regulated.

阿尔茨海默病的主要原因是β-淀粉样蛋白（Aβ）的产生和Aβ的神经毒性寡聚体形成。Aβ是淀粉样β蛋白前体（APP）在β-和γ-分泌酶的连续作用下裂解产生的代谢产物。γ-分泌酶早老素组分的突变可引起APP的交替性膜内加工，导致Aβ的异常形态，进而可导致家族性AD（FAD）。与FAD相反，散发型AD的主要原因仍不清楚。几种膜和跨膜蛋白与AD相关，并且在AD脑中观察到囊泡运输系统的破坏，这表明膜运输系统的缺陷，包括轴突囊泡运输，可能是AD发病机制的原始原因。我把这项研究集中在APP囊泡运输的分析上。已知APP是驱动蛋白-1的货物受体。我们以前的研究表明，APP通过JIP 1介导与KLC相关。此外，APP囊泡转运的中断增加了神经毒性Aβ的产生。然而，APP和驱动蛋白-1的关联如何被调节的分子机制仍不清楚。我们详细揭示了JIP 1和KLC之间的关联，并提出了如何调节这种关联。