Department of Pathophysiology, Neuroscience Center, Hebei Medical University, Shijiazhuang, P.R. China.
Central Laboratory, The Second Hospital of Hebei Medical University, Shijiazhuang, P.R. China.
J Alzheimers Dis. 2018;66(4):1731-1743. doi: 10.3233/JAD-180708.
Alzheimer's disease (AD) is characterized by progressive impairment of learning, memory, and cognitive deficits. Glutamate is the major excitatory neurotransmitter in the central nervous system and plays an important role in learning, memory, and cognition. The homeostasis and reutilization of glutamate are dependent on astrocytic uptake by glutamate transporter-1 (GLT-1) and the subsequent glutamate-glutamine cycle. Increasing evidence showed impairments in GLT-1 expression and uptake activity and glutamate-glutamine cycle in AD. Ceftriaxone (Cef) has been reported to upregulate the expression and uptake of GLT-1. Therefore, the present study was undertaken to explore whether Cef can improve cognitive deficits of APP/PS1 mice in early stage of AD by upregulating GLT-1 expression, and then promoting the glutamate-glutamine cycle. It was shown that Cef treatment significantly alleviated the cognitive deficits measured by Morris water maze test and upregulated GLT-1 protein expression in the hippocampus of APP/PS1 mice. Particularly, the activity of glutamine synthetase (GS) and the protein expression of system N glutamine transporter 1 (SN1), which are the key factors involved in the glutamate-glutamine cycle, were significantly upregulated as well after the Cef treatment. Furthermore, inhibition of GLT-1 uptake activity by dihydrokainic acid, an inhibitor of GLT-1, blocked the Cef-induced improvement on the cognitive deficits, GS activity, and SN1 expression. The above results suggested that Cef could improve cognitive deficits of APP/PS1 mice in early stage of AD by upregulating the GLT-1 expression, GS activity, and SN1 expression, which would lead to stimulating the glutamate-glutamine cycle.
阿尔茨海默病（AD）的特征是学习、记忆和认知功能逐渐受损。谷氨酸是中枢神经系统中的主要兴奋性神经递质，在学习、记忆和认知中发挥重要作用。谷氨酸的内稳态和再利用依赖于星形胶质细胞摄取谷氨酸转运体-1（GLT-1）和随后的谷氨酸-谷氨酰胺循环。越来越多的证据表明 AD 中 GLT-1 表达和摄取活性以及谷氨酸-谷氨酰胺循环受损。头孢曲松（Cef）已被报道可上调 GLT-1 的表达和摄取。因此，本研究旨在探讨头孢曲松是否可以通过上调 GLT-1 表达，进而促进谷氨酸-谷氨酰胺循环，改善 AD 早期 APP/PS1 小鼠的认知功能障碍。结果表明，头孢曲松治疗可显著改善 APP/PS1 小鼠水迷宫测试中的认知障碍，并上调 APP/PS1 小鼠海马区 GLT-1 蛋白表达。特别是，谷氨酸-谷氨酰胺循环中的关键因素谷氨酰胺合成酶（GS）和系统 N 型谷氨酸转运体 1（SN1）的活性和蛋白表达也显著上调。此外，GLT-1 摄取抑制剂二氢酮酸阻断了头孢曲松诱导的认知障碍、GS 活性和 SN1 表达的改善。上述结果表明，头孢曲松通过上调 GLT-1 表达、GS 活性和 SN1 表达改善 AD 早期 APP/PS1 小鼠的认知障碍，从而刺激谷氨酸-谷氨酰胺循环。
