TRPC6在反复低血糖致认知损害中的作用及其机制

Recurrent asymptomatic hypoglycemia (RH) often occurs in the treatment of diabetes mellitus, which is prone to damage cognitive function. Mitochondrial biosynthesis mediated by AMPK/Sirt1/PGC-1α pathway in central neurons is crucial to maintain neuronal excitability and normal cognitive function, but whether RH affects mitochondrial function and its mechanism remains unclear. Transient receptor potential channel TRPC6 is widely expressed in the brain, and it mediates calcium signaling affecting cognitive function. Our previous work has shown that RH can impair spatial memory and damage TRPC6 with its related neurons in cortex and hippocampus, but how TRPC6 abnormalities affect cognitive function and its mechanism is still not clear. To this end, we propose a theoretical hypothesis that RH can impair the function of TRPC6 and disrupt Ca2+ signaling homeostasis in neurons, which leads to the impairment of mitochondrial biosynthesis mediated by AMPK/Sirt1/PGC-1α pathway, resulting in neuronal dysfunction and cognitive impairment. In this project, wild-type and APP/PS1 mice were used as subjects, and in vivo two-photon central imaging techniques were used to reveal the role and mechanism of TRPC6 in diabetic RH, providing a scientific basis for preventing cognitive dysfunction related to diabetes treatment.

糖尿病治疗中常发生无症状性反复性低血糖（RH），其频繁出现易损害认知功能。中枢神经元AMPK/Sirt1/PGC-1α通路介导的线粒体生物合成对维持神经元兴奋性及正常认知功能十分关键，但RH是否影响线粒体功能及其机制尚不清楚。已知瞬时受体电位通道TRPC6在大脑广泛表达，其介导的钙信号影响认知功能。我们前期工作显示RH可使大脑空间记忆功能障碍，皮层及海马TRPC6及相关神经元发生损害，但TRPC6异常如何影响认知功能及其机制并不明确。为此，我们提出理论假设：RH可损害神经元TRPC6功能，使神经元Ca2+紊乱，引起AMPK/Sirt1/PGC-1α通路介导的线粒体生物合成障碍，导致神经元功能障碍及认知功能损害。本项目以野生型和APP/PS1小鼠为对象，利用活体双光子中枢成像等技术，揭示TRPC6在糖尿病RH过程中的作用及机制，为防治糖尿病治疗相关的认知功能异常提供科学依据。

轻/中度低血糖反复发作(RH)是糖尿病病人降血糖治疗过程中常见的临床并发症。低血糖发作损害糖尿病病人对抗调节反应，从而易造成反复发作。严重低血糖发作损害糖尿病病人的认知功能，显著提高罹患老年痴呆症（AD）的风险。与严重低血糖发作相比，RH的发作频率更高且不易被病人察觉，因此需格外关注。本研究探讨了RH对糖尿病病人，尤其是对有AD遗传风险的糖尿病病人认知功能的影响和潜在机制。RH通过抑制激活瞬时受体电位通道C6（TRPC6）介导的胞浆游离Ca2+瞬变，抑制5'-单磷酸腺苷活化的蛋白激酶（AMPK）激活，从而上调Drp1在Ser616位点的磷酸化，抑制Ser637位点磷酸化，引起糖尿病小鼠海马神经元线粒体过度分裂，损害线粒体氧化磷酸化功能和神经元能量平衡，导致认知功能障碍的出现。RH损害大脑GLUT3介导的葡萄糖摄取，并进一步抑制TRPC6表达，进而引发神经元线粒体功能障碍，从而加速糖尿病APP/PS1小鼠认知功能障碍的进展。金丝桃素激活TRPC6可显著改善RH诱导的认知功能障碍，其机制为TRPC6介导的胞浆钙内流通过激活AMPK来抑制RH发作引起的糖尿病小鼠海马线粒体分裂。本研究结果提示，糖尿病病人降血糖治疗过程中应采取“宁高勿低”的策略，避免RH发生，对糖尿病患者的血糖控制至关重要，TRPC6/GLUT3是延缓糖尿病患者痴呆发病的有效靶点之一。本研究结论为糖尿病治疗过程中引起认知功能损伤的防治提供了理论依据，具有重要的临床应用价值。