光刺激对阿尔茨海默病模型小鼠认知障碍的治疗作用及其机制中GSK-3β相关信号通路作用的研究

阿尔茨海默病是神经系统退行性疾病，是痴呆最常见类型。我们前期研究发现在AD模型小鼠中，Aβ可以通过抑制海马和皮层BK通道的活性发挥毒性作用，光刺激可以易化BK通道的活性，改善认知。进一步探究BK通道在AD中的作用及其下游信号通路的过程中，我们发现小胶质细胞中BK通道活性在其超活化和迁移中发挥重要作用。过度激活的小胶质细胞会减少IGF-1的释放，下调Akt，增加GSK-3β活性。正常的GSK-3β功能与BK通道活性密切相关。另一方面，Aβ还可以通过胰岛素/Akt信号通路过度激活GSK-3β。而激活的GSK-3β反过来又可以增加Aβ的沉积，形成恶性循环。GSK-3β活性还可影响tau蛋白过度磷酸化，突触丢失和神经元死亡。且有研究提示光刺激可以调节GSK-3β活性。因此，我们推测GSK-3β为AD发病机制中的枢纽性环节，光刺激可以通过抑制GSK-3β的活性达到治疗AD的目的。

Alzheimer's disease is a neurodegenerative disease and is the major type of dementia. Our previous study found that in the AD model mice, Aβ can play a toxic effect by inhibiting the activity of the BK channel in the hippocampus and cortex, and photic stimulation can facilitate BK channel and improve AD syndrome. In the process of exploring the role of BK channels in AD and its downstream signaling pathways, we found that BK channel activity in microglia plays an important role in the activation and migration of microglia. Overexpression of microglia can reduce the release of IGF-1, down-regulate Akt and increase the activity of GSK3β. And normal GSK3β function is closely related to BK channel activity.On the other hand, Aβ can over-activate GSK3β through the insulin / Akt signaling pathway. The activated GSK-3β in turn can increase the deposition of Aβ, forming a vicious cycle. GSK-3β activity can also affect tau hyperphosphorylation, synaptic loss and neuronal death. And, studies have shown that photic stimulation can regulate GSK-3β activity. Therefore, we speculate that GSK3β is a pivotal part of the pathogenesis of AD, photic stimulation can achieve the goal of treating AD by inhibiting the activity of GSK3β.