SNX15 Regulates Cell Surface Recycling of APP and Aβ Generation.
SNX15 Regulates Cell Surface Recycling of APP and Aβ Generation.
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DOI：
10.1007/s12035-015-9306-z
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发表时间：
2016-08
影响因子：
5.1
通讯作者：
Zhang YW
中科院分区：
文献类型：
--
作者：
Feng T;Niu M;Ji C;Gao Y;Wen J;Bu G;Xu H;Zhang YW
淀粉样蛋白-β (A(β))肽在阿尔茨海默病（AD）的发病过程中起重要作用，由淀粉样蛋白-β前体蛋白（APP）通过β-位点APP切割酶1 （BACE1）和γ-分泌酶的序列蛋白水解裂解产生。APP、BACE1和γ-分泌酶的转运失调可能影响Aβ的产生和疾病的发病机制。已知分选连接蛋白15 （SNX15）调节蛋白质运输。本研究报告SNX15在小鼠神经元和星形胶质细胞中大量表达。此外，我们发现尽管不影响APP、BACE1和γ-分泌酶组分的蛋白水平以及BACE1和γ-分泌酶的活性，但SNX15的过表达和下调分别减少和促进了a - β的产生。此外，我们发现SNX15的过表达通过加速APP循环增加了细胞表面的APP蛋白水平，而SNX15的下调具有相反的作用。最后，我们发现通过腺相关病毒（adeno-associated virus， AAV）感染在海马齿状回外源性表达人SNX15可以显著降低APPswe/PSEN1dE9双转基因AD模型小鼠海马的Aβ病理，改善短期工作记忆。综上所述，我们的研究结果表明SNX15调节APP到细胞表面的再循环，从而调节其生成Aβ的过程。
Amyloid-β (A(β) peptide plays an essential role in the pathogenesis of Alzheimer's disease (AD) and is generated from amyloid-β precursor protein (APP) through sequential proteolytic cleavages by β-site APP cleaving enzyme 1 (BACE1) and γ-secretase. Trafficking dysregulation of APP, BACE1 and γ-secretase may affect Aβ generation and disease pathogenesis. Sorting nexin 15 (SNX15) is known to regulate protein trafficking. Here we report that SNX15 is abundantly expressed in mouse neurons and astrocytes. In addition, we show that although not affecting the protein levels of APP, BACE1 and γ-secretase components and the activity of BACE1 and γ-secretase, overexpression and downregulation of SNX15 reduces and promotes Aβ production, respectively. Furthermore, we find that overexpression of SNX15 increases APP protein levels in cell surface through accelerating APP recycling, whereas downregulation of SNX15 has an opposite effect. Finally, we show that exogenous expression of human SNX15 in the hippocampal dentate gyrus by adeno-associated virus (AAV) infection can significantly reduce Aβ pathology in the hippocampus and improve short-term working memory in the APPswe/PSEN1dE9 double transgenic AD model mice. Together, our results suggest that SNX15 regulates the recycling of APP to cell surface and thus its processing for Aβ generation.