硫化氢对内质网应激诱导tau过度磷酸化和学习记忆障碍的抑制作用及机制

Multivariate analysis have shown that phosphorylation of tau protein and neurofibrillary tangles were closely related to Alzheimer-like pathological changes, rather than Aβ deposition. Thus, AD therapy trend was moved from Aβ to tau. Studies have shown that endoplasmic reticulum stress induced hyperphosphorylation of tau and learning and memory deficits via activation of GSK-3β, and hydrogen sulfide reduced the secretion of Aβ42 by activating PI3K/AKT pathway and inhibited learning and memory impairment in mice. However, the roles and mechanisms of hydrogen sulfide on endoplasmic reticulum stress-induced tau hyperphosphorylation and learning and memory deficits remain unclear. We previously found that hydrogen sulfide inhibited Alzheimer-like tau pathology induced by endoplasmic reticulum stress. The project intends to explore the effects of hydrogen sulfide on the activity of PI3K/AKT signaling pathway induced by endoplasmic reticulum stress, and clear the effects of hydrogen sulfide on GSK-3β activity, tau protein phosphorylation levels and learning and memory induced by endoplasmic reticulum stress, and clarify the relationship among endoplasmic reticulum stress, PI3K/AKT/GSK-3β signal pathway activity, tau protein phosphorylation levels and the spatial memory impairment using confocal, western blot, real-time quantitative PCR, RNAi technology in cells and animals. The project will provide new ideas for prevention and treatment of AD.

多因素分析显示，磷酸化的tau蛋白和神经原纤维缠结与阿尔茨海默样病理变化密切相关，而非Aβ沉积，故AD治疗趋势从Aβ转向tau蛋白。研究表明内质网应激通过激活GSK-3β引起tau蛋白过度磷酸化和学习记忆障碍；硫化氢通过激活PI3K/AKT通路减少Aβ42分泌，减轻鼠学习记忆损伤，但对内质网应激诱导tau蛋白过度磷酸化和学习记忆障碍中的作用及确切的机制，仍不清楚。我们前期发现硫化氢拮抗内质网应激诱导AD样tau病理。本项目拟在细胞和AD鼠水平采用激光共聚焦、免疫印迹、qPCR、RNAi等技术，探讨硫化氢对内质网应激诱导PI3K/AKT信号通路活性变化的影响，明确硫化氢对内质网应激诱导GSK-3β活性、tau蛋白磷酸化水平及学习记忆能力变化的影响，阐明内质网应激、PI3K/AKT/GSK-3β通路活性、tau蛋白磷酸化水平以及学习记忆障碍之间的关系。本项目的开展将为AD防治提供新思路。

多因素分析显示，磷酸化的tau蛋白和神经原纤维缠结与阿尔茨海默样病理变化密切相关，而非Aβ沉积，故AD治疗趋势从Aβ转向tau蛋白。研究表明内质网应激通过激活GSK-3β引起tau蛋白过度磷酸化和学习记忆障碍；硫化氢通过激活PI3K/AKT通路减少Aβ42分泌，减轻鼠学习记忆损伤，但对内质网应激诱导tau蛋白过度磷酸化和学习记忆障碍中的作用及确切的机制，仍不清楚。本项目在细胞和动物水平采用激光共聚焦、免疫印迹、水迷宫等技术，研究发现：（1）硫化氢抑制内质网应激；（2）硫化氢抑制内质网应激诱导的GSK-3β激活；（3）硫化氢抑制内质网应激诱导的tau蛋白过度磷酸化；（4）内质网应激通过激活GSK-3β引起tau蛋白过度磷酸化；（5）硫化氢减轻内质网应激所致的学习记忆障碍；（6）硫化氢减轻内质网应激对PI3K/AKT活性的抑制作用；（7）内质网应激通过抑制PI3K/AKT的活性，激活GSK-3β，从而诱导tau蛋白过度磷酸化和学习记忆障碍。本项目采用多种技术阐明了硫化氢在内质网应激诱导tau蛋白过度磷酸化和学习记忆障碍中的作用及机制，研究成果为临床AD防治提供新思路和新靶点。