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Ceftriaxone regulates glutamate production and vesicular assembly in presynaptic terminals through GLT-1 in APP/PS1 mice
Neurobiology of Learning and Memory ( IF 2.2 ) Pub Date : 2021-06-18 , DOI: 10.1016/j.nlm.2021.107480
ShuJuan Fan 1 , Li Li 2 , XiaoHui Xian 1 , LiRong Liu 1 , JunXia Gao 1 , WenBin Li 1
Affiliation  

Perturbations in the glutamate–glutamine cycle and glutamate release from presynaptic terminals have been involved in the development of cognitive deficits in Alzheimer’s disease (AD) patients and mouse models. Glutamate transporter-1 (GLT-1) removes glutamate from the synaptic cleft and transports it into astrocytes, where it is used as substrate for the glutamate–glutamine cycle. Ceftriaxone has been reported to improve cognitive deficits in AD mice by increasing GLT-1 expression, glutamate transformation to glutamine, and glutamine efflux from astrocytes. However, the impact of ceftriaxone on glutamine metabolism in neurons is unknown. The present study aimed to investigate whether ceftriaxone regulated the production and vesicular assembly of glutamate in the presynaptic terminals of neurons and to determine GLT-1 involvement in this process. We used the amyloid precursor protein (APP)/presenilin-1 (PS1) AD mouse model and GLT-1 knockdown APP/PS1 (GLT-1+/−/APP/PS1) mice. The expression levels of sodium-coupled neutral amino-acid transporter 1 (SNAT1) and vesicular glutamate transporters 1 and 2 (VGLUT1/2) were analyzed by immunofluorescence and immunohistochemistry staining as well as by Western blotting. Glutaminase activity was assayed by fluorometry. Ceftriaxone treatment significantly increased SNAT1 expression and glutaminase activity in neurons in APP/PS1 mice. Similarly, VGLUT1/2 levels were increased in the presynaptic terminals of APP/PS1 mice treated with ceftriaxone. The deletion of one GLT-1 allele in APP/PS1 mice prevented the ceftriaxone-induced upregulation of SNAT1 and VGLUT1/2 expression, indicating that GLT-1 played an important role in ceftriaxone effect. Based on the role of SNAT1, glutaminase, and VGLUT1/2 in the glutamate–glutamine cycle in neurons, the present results suggested that ceftriaxone improved the production and vesicular assembly of glutamate as a neurotransmitter in presynaptic terminals by acting on GLT-1 in APP/PS1 mice.



中文翻译:

头孢曲松通过 APP/PS1 小鼠中的 GLT-1 调节突触前末端的谷氨酸产生和囊泡组装

谷氨酸-谷氨酰胺循环的扰动和突触前末端的谷氨酸释放与阿尔茨海默病 (AD) 患者和小鼠模型认知缺陷的发展有关。谷氨酸转运蛋白-1 (GLT-1) 从突触间隙中去除谷氨酸并将其转运到星形胶质细胞中,在星形胶质细胞中用作谷氨酸-谷氨酰胺循环的底物。据报道,头孢曲松可通过增加 GLT-1 表达、谷氨酸转化为谷氨酰胺和星形胶质细胞的谷氨酰胺流出来改善 AD 小鼠的认知缺陷。然而,头孢曲松对神经元谷氨酰胺代谢的影响尚不清楚。本研究旨在调查头孢曲松是否调节神经元突触前末端谷氨酸的产生和囊泡组装,并确定 GLT-1 参与这一过程。+/-/APP/PS1) 鼠标。通过免疫荧光和免疫组织化学染色以及蛋白质印迹分析钠偶联中性氨基酸转运蛋白 1 (SNAT1) 和囊泡谷氨酸转运蛋白 1 和 2 (VGLUT1/2) 的表达水平。通过荧光法测定谷氨酰胺酶活性。头孢曲松治疗显着增加了 APP/PS1 小鼠神经元中 SNAT1 的表达和谷氨酰胺酶活性。同样,用头孢曲松治疗的 APP/PS1 小鼠突触前末端的 VGLUT1/2 水平增加。APP/PS1小鼠中一个GLT-1等位基因的缺失阻止了头孢曲松诱导的SNAT1和VGLUT1/2表达上调,表明GLT-1在头孢曲松效应中起重要作用。基于 SNAT1、谷氨酰胺酶和 VGLUT1/2 在神经元谷氨酸-谷氨酰胺循环中的作用,

更新日期:2021-06-23
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