线粒体内质网桥接在糖尿病认知障碍中对APP转运调节作用的研究

糖尿病是造成认知功能障碍的独立危险因素，可加重脑内淀粉样蛋白的沉积，然而其扰乱Aβ分泌的机制未明。我们的预实验结果提示，高血糖可能通过干扰APP在细胞器之间的转运而扰乱Aβ的分泌过程，其具体的分子机制还有待深入探讨。为此我们提出假说：糖尿病可能减低泛素连接酶MITOL的表达，致使线粒体内质网桥接障碍，减弱线粒体去乙酰化酶Sirt3对内质网伴侣蛋白GRP78的去乙酰化作用，使APP从内质网到高尔基体的转运增多，最终导致Aβ分泌增加。为验证这一假说，我们将利用高糖干预过表达APP的CHO细胞系，C57BL/KsJ db/db小鼠糖尿病模型，通过过表达、RNA干扰、慢病毒感染等手段干预线粒体内质网桥接过程，明确在糖尿病中，线粒体内质网桥接对APP转运和Aβ分泌的调节作用。本研究将从细胞器之间的相互作用这一新的视角展开Aβ分泌调节的研究，将为揭示糖尿病认知功能障碍的机制提供新的思路。

Clinical studies demonstrated diabetes as an independent cause of cognitive dysfunction. One of the explain is that diabetes aggravates the deposition of βamyloid in the brain, exacerbating cognitive impairment. However, the mechanism of diabetes induced Aβ secretion disturbance is still unknown. Our preliminary experiment suggests diabetes may disrupt the secretion of Aβ by interfering with APP trafficking between endoplasmic reticulum and Golgi apparatus， while the molecular mechanism remains to be further discussed. Thus we put forward the hypothesis: diabetes can reduce the expression of ubiquitin ligase MITOL resulting in obstacles of tethering between mitochondria and endoplasmic reticulum, reducing the deacetylation effect of mitochondrial deacetylase Sirt3 on the endoplasmic reticulum chaperone protein GRP78, which may contribute to the increase of APP trafficking from endoplasmic reticulum to Golgi apparatus and the secreation of Aβ. To test this hypothesis, we will use the CHO cell lines stably expressing human wild-type APP, C57BL/KsJ db/db mice diabetes model. By over expression, RNA interference, lentivirus infection, we will explore the influence of mitochondria and endoplasmic reticulum tethering on the regulation of APP trafficking from endoplasmic reticulum to Golgi apparatus and Aβ sereation. From the novel perspective of interaction between organelles, we will start of the study on the mechanism of regulating Aβ secretion. This will provide a new sight for discovering the mechanism of diabetic cognitive dysfunction.