干预TACE/BACE平衡以减少“Aβ”毒性产物：小檗碱防治T2DM认知功能障碍的分子机制

Cognitive Impairment（MCI）and the development Alzheimer Disease(AD) caused by T2DM have been brought to public attention. Recent studies have shown that brain insulin resistance and cholinergic receptor pathway deficiency are co-workers in the development of T2DM complimented Cognitive Impairment, and the imbalance of TACE(α secretion pathway)/ BACE(β secretion pathway) induced toxicity protein “Aβ” causes Cognitive impairment. Based on previous evidence of the latest study “Berberine improving peripheral insulin resistance in T2DM by inhibition of AchE activity”，we hypothesize that: Firstly, berberine with attenuation of brain insulin resistance and mediation of TACE/BACE balance, as an inhibitor of AchE to increase the content of brain Ach by combination of neuronal membrane M receptor，activation of PKC and inhibition of BACE pathway and “Aβ” overproduction; Secondly, berberine direct effect against activation of neuronal inflammasome and release of inflammatory factors to protect GSK-3 around insulin pathway and further reduce brain “Aβ” production to improve T2DM induced Cognitive impairment. This study will adopt cell and animal models to investigate the effects of berberine on reducing the brain Aβ toxic products through repairing the damage of insulin signaling pathway and regulating the activity of receptor pathway from the cellular, molecular and whole level. It will provide evidence for molecular mechanism of berberine in the prevention of T2DM induced Cognitive impairment.

T2DM所致认知功能障碍（MCI）及发展为老年性痴呆（AD）倍受关注。新近研究显示：脑内胰岛素抵抗与胆碱能受体途径缺损共同参与T2DM 并发MCI，TACE (α分泌途径)/BACE（β分泌途径）失衡会造成Aβ在脑内沉积，引发MCI。基于前一课题小檗碱通过抑制AchE活性改善T2DM 外周组织IR的研究”，我们推测：小檗碱，一方面，作为AchE 的抑制剂，增加脑内Ach而与神经元膜上M受体结合激活PKC，遏制BACE 产生Aβ；另一方面，直接对抗神经元中炎症因子，保护以GSK-3为核心的胰岛素信号通路的畅通，进一步减少Aβ在脑中的沉积，从而改善T2DM 性MCI。本项目拟采用细胞和动物模型，从细胞、分子和整体水平探讨小檗碱通过修复损伤的胰岛素信号通路及调节胆碱能受体途径的活性、最终达到减少脑内Aβ等有毒产物的作用，以期为阐明小檗碱早期预防T2DM性MCI 的分子机制提供依据。

T2DM所致认知功能障碍（MCI）及发展为老年性痴呆（AD）倍受关注。新近研究显示：脑内胰岛素抵抗与胆碱能受体途径缺损共同参与T2DM 并发MCI，TACE (α分泌途径)/BACE（β分泌途径）失衡会造成Aβ在脑内沉积，引发MCI。基于前一课题小檗碱通过抑制AchE活性改善T2DM 外周组织IR的研究”，我们证实：小檗碱，一方面，作为AchE 的抑制剂，增加脑内Ach而与神经元膜上M受体结合激活PKC，遏制BACE 产生Aβ；另一方面，直接对抗神经元中炎症因子，保护以GSK-3为核心的胰岛素信号通路的畅通，进一步减少Aβ在脑中的沉积，从而改善T2DM 性MCI。本项目采用细胞和动物模型，从细胞、分子和整体水平探讨小檗碱通过修复损伤的胰岛素信号通路及调节胆碱能受体途径的活性、最终达到减少脑内Aβ等有毒产物的作用，初步阐明小檗碱早期预防T2DM性MCI 的分子机制。