头孢曲松钠通过调制胶质细胞谷氨酸转运体-1改善转基因AD模型小鼠学习记忆障碍的研究

The toxic effect of amyloid beta-protein (Aβ) is the principal mechanism in the development of Alzheimer’s disease (AD). Aβ decreases both the expression and function of glial glutamate transporter-1 (GLT-1), which induces the decline of glutamate uptake. The decreased glutamate uptake hinders “glutamate-glutamine cycle”, reduces glutamate cyclic utilization and its release as one of neurotransmitters, and then leads to dysfunction of synaptic transmission and neural circuit. In the end, the dysfunction of synaptic transmission and neural circuit results in learning, memory and cognitive deficits. It has been indicated by literatures and our previous studies that ceftriaxone (Cef) can specifically up-regulate GLT-1 expression and its glutamate uptake activity. According to the above reasons, we propose the hypothesis that Cef may have a potential effect to improve the learning, memory and cognitive deficits in AD patients by up-regulation of GLT-1 expression and its glutamate uptake activity, which enhances the efficiency of glutamate utilization as neurotransmitter, and then improves synaptic transmission and function of neural circuit. Based on this viewpoint, we plan first to investigate the improving effect of Cef treatment on spatial learning and memory deficits in double transgenic (amyloid precursor protein/presenilin-1) Alzheimer's disease mice. Then, the mechanisms involved in the improving effect of Cef treatment on the learning and memory deficits will be investigated in the respect of GLT-1 expression and its glutamate uptake, synaptic plasticity, and synaptic transmission. The research findings of this project will provide new knowledge and evidence for clinical study of AD prevention and treatment.

β-淀粉蛋白(Aβ)的毒性作用是阿尔茨海默病（AD）发病的中心环节，其对胶质细胞谷氨酸转运体-1（GLT-1）的表达和功能的损害，使“谷氨酸-谷氨酰胺循环”障碍，作为神经递质的谷氨酸的循环利用和释放减少，突触传递和神经环路功能异常，引起学习记忆障碍。文献报道及申请者以往的研究均表明，头孢曲松钠（Cef）可以特异性地上调 GLT-1 的表达及其对谷氨酸的摄取。因此，本课题提出应用Cef上调GLT-1的表达，增强其对谷氨酸的摄取，增加谷氨酸作为神经递质的利用效率，改善突触传递和神经环路的功能，有可能减轻或延缓AD认知功能障碍的观点。围绕此观点，首先采用行为学研究，确定Cef对APP/PS1双转基因AD模型小鼠学习记忆障碍的改善作用；在此基础上，从GLT-1的表达及其对谷氨酸的摄取功能、突触可塑性、突触传递效率等方面探讨Cef改善AD模型小鼠学习记忆障碍的机制，为AD的防治研究提供新依据。

研究表明，谷氨酸转运体-1（GLT-1）的表达及功能障碍在AD患者及AD模型动物认知功能障碍中发挥重要作用。β-内酰胺类药物头孢曲松钠（Cef）可增加GLT-1的表达及其对谷氨酸的摄取，从而在局部或全脑缺血动物模型以及神经退行性疾病中发挥脑保护作用。但是，Cef是否可通过上调GLT-1的表达及功能发挥抗AD作用尚不清楚。因此，本课题研究Cef是否能够上调APP/PS1 AD模型小鼠GLT-1表达和功能，是否能够改善APP/PS1 AD模型小鼠的学习记忆障碍、及其发挥抗AD作用的机制。结果发现：①Cef可改善AD早期APP/PS1小鼠的学习记忆能力障碍。②Cef可以上调APP/PS1小鼠海马CA1区GLT-1蛋白的表达和功能。③Cef可改善APP/PS1 AD小鼠海马谷氨酸-谷氨酰胺循环。④Cef改善APP/PS1小鼠海马神经元突触的丢失。这些结果表明，Cef可通过上调GLT-1的表达和功能，促进谷氨酸-谷氨酰胺循环，提高谷氨酸作为神经递质的再利用效率，减轻神经突触的丢失，进而发挥抗AD认知功能障碍的作用。这些发现为应用Cef防治AD的临床应用研究提供了实验依据和思路。