GLP-1通过激活神经系统胰岛素信号通路改善Alzheimer病的机制研究

Growing evidence supported that type 2 diabetes mellitus(T2DM)patients have a greater risk of developing Alzheimer’s disease (AD), suggesting that T2DM and AD shared some common pathogenic mechanisms. It has been reported that defective insulin signaling occurs in the brains of not only T2DM patients, but also AD patients, while GLP-1 mimetics has been found to improve cognition in AD patients via enhancing insulin signaling, suggesting a crucial role of insulin signaling in the pathogenesis of AD. Previous studies have confirmed that, there were “β cells” which could secrete insulin in the nervous system, and the insulin they secreted might play a vital role in activating and maintaining the insulin signaling pathway in nervous system. We hypothesize that, the therapeutic effect of GLP-1 might be due to that GLP-1 promote the insulin secretion of “β cells” in the nervous system, or inhibit the apoptosis and promote the proliferation of the “β cells”, but the molecular mechanism still needs further studies. The current project will use Tet-OFF system to prepare mice with neuronal insulin deficiency, and explore the effect of GLP-1 on animals’ cognitive function, and the effect of GLP-1 on the proliferation, apoptosis, and insulin secretion of neurons, so as to further elucidate the molecular mechanism of GLP-1’s role in improving AD.

流行病学显示，2型糖尿病（T2DM）患者的Alzheimer病（AD）发病风险明显增高，说明T2DM与AD发生可能存在共同的机制。研究发现，在T2DM和AD患者中均存在神经系统胰岛素信号通路受损，而GLP-1类似物可通过增强胰岛素信号通路改善AD患者的认知，表明神经系统胰岛素信号通路在AD发病中起着十分重要的作用。既往研究证实，神经系统内存在能够分泌胰岛素的“β细胞”，其所分泌的胰岛素对神经系统内胰岛素通路的激活和维持可能起着关键性的作用。我们推测，GLP-1的神经元保护作用可能是由于GLP-1促进神经细胞中“β细胞”的胰岛素分泌，或者减少凋亡促进增殖，但具体分子机制有待深入研究。本课题拟通过Tet-OFF系统制备神经系统内胰岛素缺乏小鼠，观察GLP-1对认知的影响，并通过检测神经细胞中的“β细胞”的胰岛素分泌、增殖及凋亡从而进一步明确GLP-1改善AD的分子机制。

流行病学资料显示，2型糖尿病时Alzheimer病发病风险显著增高，但病因不明。既往研究显示，神经细胞在特定条件下可分泌胰岛素，而2型糖尿病大脑中存在胰岛素缺乏。本课题首先观察到神经细胞在高糖及GLP-1环境中，其胰岛素合成相关基因及胰岛素基因表达增加，胰岛素阳性神经细胞数量增加，说明神经细胞在特定情况下具备分泌胰岛素的能力。其次，本课题构建胰岛素合成相关基因干扰腺病毒，海马定位注射，以此阻断大脑神经细胞胰岛素合成，同时外周注射GLP-1，结果发现GLP-1可改善2型糖尿病小鼠认知状态，提高大脑胰岛素水平，但海马内注射干扰腺病毒阻断神经细胞胰岛素合成后，小鼠大脑内胰岛素降至极低水平，且GLP-1改善2型糖尿病小鼠认知状态的作用消失，证实GLP-1的认知改善作用是通过促进神经细胞中“β细胞”的胰岛素分泌来实现。