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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的神经毒性寡聚体的形成。β是一种代谢产物，由淀粉样蛋白前体(APP)在β-和γ-分泌酶的连续作用下裂解而产生。γ-分泌酶的早老素成分突变可引起APP的膜内交替加工，导致Aβ的异常形态形成，进而导致家族性AD(FAD)。与FAD不同，散发性AD的主要原因尚不清楚。几种膜蛋白和跨膜蛋白与AD有关，在AD脑中观察到囊泡运输系统的破坏，提示膜运输系统的缺陷，包括轴突囊泡运输，可能是AD发病的原始原因。我将研究重点放在了对APP泡泡交易的分析上。APP是已知的激动素-1的受体。我们之前的研究表明，APP通过JIP1中介与KLC相关。此外，APP囊泡转运蛋白的破坏增加了神经毒性Aβ的产生。然而，APP和Kinesin-1相互作用的分子机制仍不清楚。我们详细揭示了JIP1和KLC之间的关联，并提出了如何调节这种关联。