Furin通过内体转运途径调节APP降解并参与阿尔茨海默病

Furin是一种来往于内体（endosome）和高尔基体的前体蛋白转化酶。Furin由于影响ADAM10和BDNF的功能，因而与阿尔茨海默病（Alzheimer Disease, AD）关系密切。前期实验发现，Furin过表达的细胞中APP和Abeta水平降低而自噬标记物LC3II水平增高；抑制ADAM10后Furin仍然能促进APP降解。而沉默AP2M1（内吞相关蛋白）或vps34（内体循环蛋白）后， Furin对APP的降解明显抑制。我们推测Furin具有新功能：即通过内体转运途径调节APP降解和Abeta水平。为此，我们将利用分子和细胞生物学以及furin条件敲除等手段研究:（1）在离体细胞中证实内体转运相关蛋白参与了Furin对APP降解调节；（2）在furin条件敲除鼠中验证APP内体转运途径的改变参与了AD病理改变及学习记忆障碍；并探索敲除鼠对神经元发育和可塑性的影响。

Furin is a pro-protein convertase that is trafficked between endosome and trans-Golgi networks. The substrates of Furin include ADAM10 and BDNF, which are closely associated with Alzheimer Disease (AD). However, our preliminary study has shown that Furin overexpression reduced APP protein and Abeta levels with the concomitant elevation of autophagic marker LC3II protein levels; and the effect of Furin on APP degradation could not be blocked by ADAM10 inhibitor. We further found that Furin-mediated APP degradation was largely prevented in cells with the silencing of adaptor protein AP2M1 or endosomal trafficking-related protein Vps34. We speculate that Furin might have novel roles in APP processing by regulating the endosomal trafficking. Therefore, using cellular and molecular methods and furin conditional knockout mice, we aimed to (1) Verify that Furin regulates endosomal trafficking of APP through AP2M1- and Vps34-associated mechanisms in vitro; (2) In furin conditional knockout mice, validate that Furin-mediated regulation of endosomal trafficking of APP is associated with pathological alterations of AD. Meanwhile, dissect the potential mechanisms of the alterations of synaptic plasticity by Furin knockout.