金钗石斛总生物碱调控PI3K/Akt/GSK-3β通路抑制Tau蛋白过度磷酸化在AD中的机制研究

阿尔茨海默病（AD）发病机制不明，尚缺有效治疗药物。中医药理论认为“AD以肾虚为本质，胰（脾）病为起始”，补益中药有防治AD的作用。金钗石斛为补益中药，我们前期发现其有效成分金钗石斛总生物碱（DNLA）是胰岛素增敏剂，可改善学习记忆能力，与其激活Akt，降低Tau蛋白过度磷酸化，抑制凋亡有关。而PI3K/Akt/GSK-3β通路作为胰岛素相关通路还在AD中调节Tau蛋白磷酸化，是补益中药发挥神经保护作用的关键。故推测DNLA通过PI3K/Akt/GSK-3β通路抑制Tau蛋白过度磷酸化，从而延缓AD的病理改变。项目拟采用3×Tg-AD模式小鼠进一步验证DNLA对AD的作用，检测脑糖代谢和PI3K/Akt/GSK-3β变化；另采用GSK-3β转染的N2a细胞分析其调控PI3K/Akt/GSK-3β抑制Tau蛋白过度磷酸化的机制。为DNLA用于AD治疗提供实验依据，也为金钗石斛开发提供新思路。

The pathogenesis of Alzheimer's disease (AD) is unclear, and there is currently no effective therapeutic drug. The theory of traditional Chinese medicine believes that AD takes kidney deficiency as the essence and pancreas (spleen) disease as the starting point. Tonic Chinese medicine can prevent and treat AD. Dendrobium nobile Lindl. is a kind of tonic Chinese medicine. We found that the active ingredient of Dendrobium nobile Lindl. alkaloid (DNLA) is an insulin sensitizer, it can improve learning and memory ability, which is related to activation of Akt, reduction of Tau protein hyperphosphorylation and inhibition of apoptosis. The PI3K/Akt/GSK-3β pathway, as an insulin-related pathway, also regulates the level of Tau protein phosphorylation in AD, which is the key to the neuroprotective effect of tonic Chinese medicine. Therefore, we speculate that DNLA inhibits the excessive phosphorylation of Tau protein through the PI3K/Akt/GSK-3β pathway, thereby delaying the pathological changes of AD. On the one hand, the project intends to further verify the effect of DNLA on AD with 3×Tg-AD model mice, and detect the changes of brain glucose metabolism and PI3K/Akt/GSK-3β. On the other hand, it will analyze the mechanism of inhibiting Tau protein hyperphosphorylation by regulating PI3K/Akt/GSK-3β with GSK-3β-transfected N2a cells. It provides experimental basis for the treatment of AD by DNLA, and also provides new ideas for the development of Dendrobium nobile.