杨桃根中DMDD对糖尿病并发AD ApoE基因多态性表达的影响及作用机制研究

Type 2 Diabetes Mellitus (T2DM) is one of the key factors leading to Alzheimer Disease. DMDD which's separated from the folk medicinal materials Averrhoa carambola L. root not only had a good hypoglycemic, improving lipid metabolism effect and reducing the levels of imflammatory factors, et al, but also down-regulate ApoE expression. Unfortunately, its mechanism remains largely unknown. Now, the ApoE gene has been identified as the major risk factor leading to AD. Down-regulating ApoE expression play an important role in preventing T2DM to AD. We discovered that DMDD not only can reduce the levels of FBG, TC and TG, but also can lower ApoE expression. Therefore, we conjecture that DMDD preventing T2DM to AD may be associated with its inhibition on ApoE expression, β-amyloid protein aggregation and Tau protein abnormal phosphorylation, or speeding up β-amyloid protein cleaning rate. So, in this research, to expound DMDD explicit cellular mechanism in preventing T2DM to AD via inhibiting the ApoE gene expression, we will investigate its protective effect and the regulatory mechanism of ApoE polymorphism for T2DM complicated with AD in vivo and in vitro used by histopathological examination, PCR, ELISA, and so on. That will provide a good theoretical basis for further clinical research for DMDD.

T2DM是导致AD发生的关键因素之一。从民间药材杨桃根分离得到的化合物DMDD有良好降血糖、改善脂质代谢、降低炎症因子水平等作用，并能下调ApoE基因表达，但机制尚未完全明确。目前，已发现ApoE基因是导致AD的主要危险因素，通过下调ApoE基因表达，对防止T2DM并发AD有重要作用。我们发现：DMDD不仅能降血糖、TC、AGEs等水平，而且还能下调ApoE基因表达。推测它可能是通过抑制ApoE ε4表达和Aβ蛋白聚集与Tau蛋白异常磷酸化；或加快Aβ清除速率，从而减缓了T2DM形成AD的过程。因此，本项目中我们从体外，以不同Aβ聚集体对PC12、SH-SY5Y细胞诱导为AD细胞模型；体内采用OA构建T2DM合并AD大鼠模型，以病理学分析、PCR、ELISA等方法，系统地研究DMDD对T2DM并发AD的作用，阐明它对ApoE基因多态性表达的调控机制，为DMDD临床研发提供坚实的理论基础

T2DM是导致AD发生的关键因素之一。从民间药材杨桃根分离得到的化合物DMDD有良好降血糖、改善脂质代谢、降低炎症因子水平等作用，并能下调ApoE ε4基因表达，但机制尚未完全明确。目前，已发现神经元凋亡和Aβ沉积是导致AD的主要危险因素，通过下调ApoE ε4基因表达，对防止T2DM并发AD有重要作用。我们发现：DMDD可能是通过抑制Bax / Bcl-2介导的线粒体膜电位紊乱逆转PC12和SH-SY5Y神经细胞的凋亡，还可抑制APP / PS1小鼠海马组织中APP、Aβ的生成，降低Aβ蛋白聚集及沉淀，使Tau蛋白异常磷酸化得到抑制，而减少Aβ及Tau蛋白异常磷酸化海马神经元的损伤，改善海马神经元的组织结构，降低炎症因子水平，提高抗氧化能力，使其逐步恢复正常的胆碱能神经递质和单胺类神经递质的生成及代谢，阻碍凋亡的发生，从而达到抗痴呆作用，在DMDD对ApoE ε4基因表达检测中发现无显著性差异。