Ceftriaxone ameliorates tau phosphorylation and mislocalization in APP/PS1 AD mice by inhibiting endoplasmic reticulum stress

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology Pub Date : 2025-07-25 DOI:10.1016/j.neuropharm.2025.110600

Niu-Niu Feng , Li Li , Li-Zhe Liu , Ruo-Bing He , Xiao-Hui Xian , Li-Rong Liu , Yu-Yan Hu , Wen-Bin Li

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引用次数: 0

Abstract

Tau phosphorylation and mislocalization are hallmark pathological features of Alzheimer's disease (AD), with endoplasmic reticulum stress (ERS) contributing to tauopathy. We previously showed that ceftriaxone (Cef) improves cognition in APP/PS1 AD mice through regulating GLT-1-mediated glutamate homeostasis. Here, we examined Cef's neuroprotection against ERS-related tauopathy. C57BL/6J and APP/PS1 AD mice were used. Cognitive functions were assessed by new object recognition (NOR), new location recognition (NLR) and Morris water maze (MWM) tests. Hippocampal synaptosomes were isolated using the Syn-PER™ Synaptic Protein Extraction Kit. Western blot analysis evaluates the protein levels of ERS markers, total and phosphorylated tau (Ser396/Ser262/Thr181), and Gsk3β. Transmission electron microscopy examined the endoplasmic reticulum ultrastructural changes of the hippocampus. Confocal 3D-reconstructed imaging assessed the phosphorylated tau (Ser396) distribution on the dendrites in the hippocampal region. The results showed that Cef treatment effectively reduced protein levels of ERS markers and restored endoplasmic reticulum ultrastructural integrity of hippocampus. Simultaneously, Cef treatment significantly alleviated tau phosphorylation levels, decreased accumulation of total and phosphorylated tau in synaptosomes, reduced phosphorylated tau (Ser396) distribution in dendritic compartments and inhibited Gsk3β activity in the hippocampus of APP/PS1 AD mice. Tunicamycin, a promoter of ERS, exacerbated cognitive impairments, tau phosphorylation levels and mislocalization, and Gsk3β activity, and notably, this exacerbation was inhibited by Cef treatment. Simultaneously, the ERS activation significantly inhibited Cef's above benefits on APP/PS1 AD mice. In conclusion, Cef improves cognitive impairment by alleviating ERS, decreasing Gsk3β activity, and reducing tau phosphorylation and mislocalization in the hippocampus of APP/PS1 AD mice.

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头孢曲松通过抑制内质网应激改善APP/PS1 AD小鼠tau磷酸化和错定位。

Tau磷酸化和定位错误是阿尔茨海默病（AD）的标志性病理特征，内质网应激（ERS）导致Tau病变。我们之前的研究表明，头孢曲松（Cef）通过调节glt -1介导的谷氨酸稳态来改善APP/PS1 AD小鼠的认知。在这里，我们研究了Cef对ers相关牛头病的神经保护作用。采用C57BL/6J和APP/PS1 AD小鼠。采用新目标识别（NOR）、新位置识别（NLR）和Morris水迷宫（MWM）测试评估小鼠的认知功能。使用Syn-PER™突触蛋白提取试剂盒分离海马突触体。Western blot分析评估ERS标记物、总tau蛋白和磷酸化tau蛋白（Ser396/Ser262/Thr181）以及GSK3β的蛋白水平。透射电镜观察海马内质网超微结构变化。共聚焦3d重建成像评估了磷酸化的tau （Ser396）在海马区树突上的分布。结果表明，Cef治疗可有效降低海马内质网标记物蛋白水平，恢复海马内质网超微结构完整性。同时，Cef处理显著减轻了APP/PS1 AD小鼠的tau磷酸化水平，降低了突触体中总tau和磷酸化tau的积累，减少了树突室中磷酸化tau （Ser396）的分布，并抑制了海马中Gsk3β的活性。Tunicamycin是ERS的一种启动子，它会加重认知障碍、tau磷酸化水平和错误定位以及Gsk3β活性，值得注意的是，这种恶化被Cef治疗抑制。同时，ERS激活显著抑制Cef对APP/PS1 AD小鼠的上述益处。综上所述，Cef通过减轻APP/PS1 AD小鼠的ERS、降低Gsk3β活性、减少海马中tau磷酸化和错误定位来改善认知功能障碍。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Neuropharmacology 医学-神经科学

CiteScore

10.00

自引率

4.30%

发文量

288

审稿时长

45 days

期刊介绍： Neuropharmacology publishes high quality, original research and review articles within the discipline of neuroscience, especially articles with a neuropharmacological component. However, papers within any area of neuroscience will be considered. The journal does not usually accept clinical research, although preclinical neuropharmacological studies in humans may be considered. The journal only considers submissions in which the chemical structures and compositions of experimental agents are readily available in the literature or disclosed by the authors in the submitted manuscript. Only in exceptional circumstances will natural products be considered, and then only if the preparation is well defined by scientific means. Neuropharmacology publishes articles of any length (original research and reviews).