He Chengkang, Gao Peng, Cui Yuanting, Li Qiang, Li Yingsha, Lu Zongshi, Ma Huan, Zhao Yu, Li Li, Sun Fang, Chen Xiaowei, Jia Hongbo, Liu Daoyan, Yang Gangyi, Zheng Hongting, Zhu Zhiming
Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, Chongqing Institute of Hypertension, Army Medical University, Chongqing, China.
Brain Research Center, Army Medical University, Chongqing, China.
Clin Transl Med. 2020 Oct;10(6):e205. doi: 10.1002/ctm2.205.
Recurrent moderate hypoglycemia (RH), a major adverse effect of hypoglycemic therapy in diabetic patients, is one of the main risk factors for cognitive impairment and dementia. Transient receptor potential canonical channel 6 (TRPC6) is a potential therapeutic target for Alzheimer's disease (AD) and its expression is highly regulated by glucose concentration.
To investigate whether RH regulates the expression of TRPC6 in brain and whether TRPC6 dysfunction can drive hypoglycemia-associated cognitive impairment in diabetes, and reveal the underlying mechanism.
Histological staining, in vivo two-photon Ca imaging, and behavioral tests were used to measure neuronal death, brain network activity, and cognitive function in mice, respectively. High-resolution respirometry and transmission electron microscope were used to assess mitochondrial structure and function. Intracellular calcium measurement and molecular biology techniques were conducted to uncover the underlying mechanism.
Here, we report that the expression of TRPC6 in hippocampus was specifically repressed by RH in streptozocin-induced type 1 diabetic mice, but not in nondiabetic mice. TRPC6 knockout directly leads to neuron loss, neuronal activity, and cognitive function impairment under diabetic condition, the degree of which is similar to that of RH. Activation of TRPC6 with hyperforin substantially improved RH-induced cognitive impairment. Mechanistically, TRPC6 inhibited mitochondrial fission in the hippocampus of diabetic mice undergoing RH episodes by activating adenosine 5'-monophosphate-activated protein kinase, and TRPC6-mediated cytosolic calcium influx was required for this process. Clinically, dysfunction of TRPC6 was closely associated with cognitive impairment in type 2 diabetic patients with RH.
Our results indicate that TRPC6 is a critical sensitive cation channel to hypoglycemia and is a promising target to prevent RH-induced cognitive impairment by properly orchestrating the mitochondrial dynamics in diabetic patients.
反复中度低血糖（RH）是糖尿病患者降糖治疗的主要不良反应之一，是认知障碍和痴呆的主要危险因素。瞬时受体电位阳离子通道6（TRPC6）是阿尔茨海默病（AD）的潜在治疗靶点，其表达受葡萄糖浓度高度调节。
研究RH是否调节大脑中TRPC6的表达，以及TRPC6功能障碍是否会导致糖尿病患者低血糖相关的认知障碍，并揭示其潜在机制。
分别采用组织学染色、体内双光子钙成像和行为测试来测量小鼠的神经元死亡、脑网络活动和认知功能。采用高分辨率呼吸测定法和透射电子显微镜评估线粒体结构和功能。进行细胞内钙测量和分子生物学技术以揭示潜在机制。
在此，我们报道在链脲佐菌素诱导的1型糖尿病小鼠中，RH特异性抑制海马体中TRPC6的表达，但在非糖尿病小鼠中未出现这种情况。在糖尿病条件下，TRPC6基因敲除直接导致神经元丢失、神经元活动和认知功能受损，其程度与RH相似。贯叶连翘素激活TRPC6可显著改善RH诱导的认知障碍。机制上，TRPC6通过激活5'-单磷酸腺苷激活的蛋白激酶抑制RH发作的糖尿病小鼠海马体中的线粒体分裂，此过程需要TRPC6介导的胞质钙内流。临床上，TRPC6功能障碍与有RH的2型糖尿病患者的认知障碍密切相关。
我们的结果表明，TRPC6是对低血糖关键敏感的阳离子通道，是通过适当协调糖尿病患者的线粒体动力学来预防RH诱导的认知障碍的有前景的靶点。
