Pathogenesis of Alzheimer's disease by aberrant APP transport

阿尔茨海默病的主要原因是β-淀粉样蛋白（Aβ）的产生和Aβ的神经毒性低聚物的形成。a β是淀粉样蛋白β-蛋白前体（APP）在β-和γ-分泌酶的连续作用下裂解而产生的代谢产物。γ-分泌酶的早老素成分突变可引起APP的膜内加工，导致Aβ的异常形成，进而导致家族性AD （FAD）。与FAD相比，散发性AD的主要病因尚不清楚。几种膜和跨膜蛋白与阿尔茨海默病有关，并且在阿尔茨海默病大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，可能是阿尔茨海默病发病的原始原因。我的研究重点是分析APP的囊泡贩运。APP是已知的激酶-1受体。我们之前的研究表明APP通过JIP1介导与KLC相关。此外，APP囊泡运输的中断增加了神经毒性Aβ的产生。然而，APP和激酶-1联合调控的分子机制尚不清楚。我们详细揭示了JIP1和KLC之间的关联，并提出了这种关联是如何调控的。

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.