中文摘要：

不溶性β淀粉样蛋白（β-amyloid,Aβ）的沉积是阿尔茨海默症（Alzheimer′s disease,AD）的中心环节,Aβ是由β-分泌酶（BACE1）和γ-分泌酶顺序切割β淀粉样蛋白前体蛋白（β-amyloid precursor protein,APP）产生的,BACE1与APP在质膜、内含体/溶酶体、高尔基体反面膜囊（TGN）以及早期分泌途径之间的转运很大程度上影响了Aβ的产生.通过Western blot和免疫荧光的方法探讨了Sorting nexin12（SNX12）对Aβ产生的影响及其作用机制.Western blot结果显示过表达SNX12后,分泌到细胞外的Aβ减少,γ-分泌酶的活性及PS1、NCT、pen-2、APP和BACE1的蛋白水平没有明显变化,APP-βCTF水平降低,而下调SNX12时Aβ水平增加,与对照组相比,差异均具有统计学意义（p〈0.05）;免疫荧光结果表明,SNX12与BACE1在细胞内存在共定位,并且SNX12表达增加可以使BACE1和APP在细胞内处于同一区域的数量减少.这些结果表明,过表达SNX12通过调节BACE1在细胞内的定位,使细胞内处于同一区域的BACE1与APP的数量减少,导致经BACE1切割的APP减少,从而降低Aβ的产生.因此SNX12可能在AD的发病过程中起着一定的调节作用.

英文摘要：

The deposition of insoluble β-amyloid（Aβ） is the key link of Alzheimer′s disease（AD）.Aβ is produced by sequential proteolytic cleavage of the β-amyloid precursor protein（APP） by β-（BACE1） and γ-secretases.Aβ production is affected by the trafficking of BACE1 and APP among plasma membrane,endosome/lysosome,trans golgi network（TGN） and the early secretary pathways.Here this article used Western blot and immunofluorescence to investigate the effect of sorting nexin12（SNX12） on Aβ production and the underlying mechanism.Western blot data showed that overexpression of SNX12 resulted in a significant reduction in the levels of Aβ and APP-βCTF,but had no effect on the levels of γ-secretase components（including PS1,NCT and pen-2）,APP,and BACE1;While knockdown of SNX12 increased the level of Aβ.Furthermore,immunofluorescence data showed that SNX12 colocalized with BACE1 and overexpression of SNX12 decreased the co-localization of APP and BACE1.This study demonstrates that overexpression of SNX12 can reduce the co-localization of APP and BACE1 by re-distributing the subcellular localization of BACE1,therefore reducing the cleavage of APP by BACE1 and Aβ generation.Taken together,our results suggest that SNX12 may involve in AD pathology.