绿茶多酚抑制CASP1介导小胶质细胞表型转化的抗AD作用机制研究

Neural microenvironment mediated by Microglia (MG) M1/M2 phenotype involves in the pathogenesis and development of Alzheimer’s disease (AD). We separated and purified Green tea polyphenols (GTP) from Camellia sinensis. It was found that EGCG could cross the blood brain barrier and be distributed into the brain of AD rats to elicit the anti-AD effects. Also, we found that GTP improved the Aβ deposition and neuronal apoptosis in APP/PS1 transgenic mice. Furthermore, it was found that GTP reduced MG-M1 phenotype markers, and increased MG-M2 phenotype markers, associated with the CASP1 downregulation and the activity changes of JAK/STATs signaling. Bioinformatics predicted that GTP could specifically bind with Ile239 and Cys331 in CASP1 active inhibiting pocket. These results mentioned above suggested GTP elicited the anti-AD effects by repolarizing MG from M1 to M2 phenotype mediated by JAK/STATs signaling after binding with the active sites of CASP1 and inhibiting its activity. However, it still needed to be further studied. Taking the MG phenotype switch as the breakthrough point, to study the correlation between CASP1 and MG phenotype switch mediated via GTP inhibiting Aβ-induced neuronal apoptosis, to clarify the mechanism of GTP regulating MG phenotype switch via JAK/STAT pathway by CASP1 induced, further to clear the binding mode and key sites between GTP and CASP1 active inhibiting pocket, this study will provide new strategies and novel targets for AD therapy and the development of anti-AD drugs.

小胶质细胞(MG)M1/M2表型转化介导神经微环境参与AD发生和发展。申请者从绿茶中分离得到绿茶多酚(GTP)，发现其在AD动物脑内分布，并改善APP/PS1小鼠Aβ沉积、抑制神经元凋亡；进而发现GTP降低AD脑内MG-M1标志物，升高MG-M2标记物的同时，伴有CASP1下调和JAK/STATs通路改变；生物信息学预测GTP与CASP1活性抑制口袋中Ile239和Cys331结合，提示GTP可能与CASP1关键位点结合抑制其活性，介导JAK/STATs通路调节MG表型转化发挥抗AD作用，但尚需证实。本项目以MG表型转化为切入点，考察CASP1与GTP调控MG表型转化保护AD神经元的相关性；阐明GTP抑制CASP1介导JAK/STATs通路调控MG表型转化的分子机制；进一步明确GTP与CASP1活性抑制口袋关键位点的特异结合和作用方式，为治疗AD及研发抗AD新药提供新思路与新靶点。

小胶质细胞(MG)M1/M2表型转化介导神经微环境参与AD发生和发展。申请者从绿茶中分离.得到绿茶多酚(GTP)，发现其在AD动物脑内分布，并改善APP/PS1小鼠Aβ沉积、抑制神经元凋.亡；进而发现GTP降低AD脑内MG-M1标志物，升高MG-M2标记物的同时，伴有CASP1下调和JAK/ST.ATs通路改变；生物信息学预测GTP与CASP1活性抑制口袋中Ile239和Cys331结合，提示GTP可能.与CASP1关键位点结合抑制其活性，介导JAK/STATs通路调节MG表型转化发挥抗AD作用，但尚需.证实。本项目以MG表型转化为切入点，考察CASP1与GTP调控MG表型转化保护AD神经元的相关性.；阐明GTP抑制CASP1介导JAK/STATs通路调控MG表型转化的分子机制；进一步明确GTP与CASP1.活性抑制口袋关键位点的特异结合和作用方式，为治疗AD及研发抗AD新药提供新思路与新靶点.。