Li Fang, Zhou Shu-Ning, Zeng Xin, Li Zhen, Yang Rui, Wang Xue-Xi, Meng Bin, Pei Wei-Lin, Lu Li
School of Basic Medical Sciences, Lanzhou University, Lanzhou, 73000, Gansu, China.
The College of Traditional Chinese Medicine, Zhejiang Pharmaceutical College, Ningbo, 315000, Zhejiang, China.
Mol Neurobiol. 2022 Aug;59(8):5193-5206. doi: 10.1007/s12035-022-02776-9. Epub 2022 Jun 9.
Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by cognitive dysfunction. The glutamate (Glu) metabolic pathway may be a major contributor to the memory dysfunction associated with AD. The TWIK-related potassium channel-1 (TREK-1) protects against brain ischemia, but any specific role for the channel in AD remains unknown. In this study, we used SAMP8 mice as an AD model and age-matched SAMR1 mice as controls. We explored the trends of changes in TREK-1 channel activity and the levels of AD-related molecules in the brains of SAMP8 mice. We found that the expression level of TREK-1 increased before 3 months of age and then began to decline. The levels of Tau and Glu increased with age whereas the acetylcholine level decreased with age. α-Linolenic acid (ALA), an activator of the TREK-1 channel, significantly increased the TREK-1 level, and improved the learning and memory deficits of SAMP8 mice aged 6 months. The mechanism in play may involve the Glu metabolic pathway. After activation of the TREK-1 channel, damaged neurons and astrocytes were rescued, the levels of Glu and the N-methyl-D-aspartate receptor were downregulated, and the level of glutamate transporter-1 was upregulated. These findings suggest that TREK-1 plays a crucial role in the pathological progression of AD; activation of the TREK-1 channel improved cognitive deficits in SAMP8 mice via a mechanism that involved Glu metabolism. The TREK-1 potassium channel may thus be a valuable therapeutic target in AD patients.
阿尔茨海默病（AD）是一种以认知功能障碍为特征的进行性神经退行性疾病。谷氨酸（Glu）代谢途径可能是与AD相关的记忆功能障碍的主要促成因素。TWIK相关钾通道-1（TREK-1）可预防脑缺血，但该通道在AD中的任何特定作用仍不清楚。在本研究中，我们使用SAMP8小鼠作为AD模型，年龄匹配的SAMR1小鼠作为对照。我们探讨了SAMP8小鼠大脑中TREK-1通道活性和AD相关分子水平的变化趋势。我们发现，TREK-1的表达水平在3月龄前升高，然后开始下降。Tau和Glu的水平随年龄增长而升高，而乙酰胆碱水平随年龄增长而降低。α-亚麻酸（ALA）是TREK-1通道的激活剂，可显著提高TREK-1水平，并改善6月龄SAMP8小鼠的学习和记忆缺陷。其作用机制可能涉及Glu代谢途径。激活TREK-1通道后，受损的神经元和星形胶质细胞得到挽救，Glu和N-甲基-D-天冬氨酸受体水平下调，谷氨酸转运体-1水平上调。这些发现表明，TREK-1在AD的病理进展中起关键作用；激活TREK-1通道通过涉及Glu代谢的机制改善了SAMP8小鼠的认知缺陷。因此，TREK-1钾通道可能是AD患者有价值的治疗靶点。
