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Ceftriaxone Modulates Ubiquitination of α-Amino-3-Hydroxy-5-Methyl-4-Isoxazole Propionic Acid Receptors to Improve Long-Term Potentiation Impairment Induced by Exogenous β-Amyloid in a Glutamate Transporter-1 Dependent Manner

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Abstract

Α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs) are crucial for properties of synaptic plasticity, such as long-term potentiation (LTP). LTP impairment can occur early in the onset of Alzheimer’s disease (AD). The downregulation or decreased abundance of AMPAR expression in the postsynaptic membrane is closely associated with LTP impairment. Ceftriaxone (Cef) can improve LTP impairment in the early stages of AD in a mouse model. The purpose of this study was to explore the mechanism underlying this process from the aspects of AMPAR expression and ubiquitination degree. In this study, we found that β-amyloid (Aβ) treatment induced hippocampal LTP impairment and AMPAR downregulation and ubiquitination. Cef pretreatment ameliorated Aβ-induced hippocampal LTP impairment, reduced AMPAR ubiquitination, and increased AMPAR expression, especially in the plasma membrane, in Aβ-treated mice. Administration of USP46 siRNA and DHK (a specific blocker of glutamate transporter-1) significantly inhibited the above effects of Cef, suggesting a role for anti-AMPAR ubiquitination and upregulation of glutamate transporter-1 (GLT-1) in the Cef-induced improvements mentioned above. The above findings demonstrate that pretreatment with Cef effectively mitigated Aβ-induced impairment of hippocampal LTP by suppressing the ubiquitination process of AMPARs in a GLT-1-dependent manner. These results provide novel insights into the underlying mechanisms elucidating the anti-AD by Cef.

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Availability of Data and Materials

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

The electrophysiological experiments were greatly assisted by Professor Bing-Cai Guan, for which we express our gratitude.

Funding

This research was supported by the National Natural Science Foundation of China (Grant/Award Number: 81971007) and the Natural Science Foundation of Hebei Province and Precision Medicine Joint Fund (Grant/Award Number: H2021206021).

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Author notes

  1. Rui Jiang and Li Li contributed equally.

Authors and Affiliations

  1. Hebei Key Laboratory of Critical Disease Mechanism and Intervention, Department of Pathophysiology, Neuroscience Research Center, Hebei Medical University, 361 Zhongshan East Road, Shijiazhuang, 050017, People’s Republic of China

    Rui Jiang, Lizhe Liu, Lirong Liu, Xiaohui Xian & Wenbin Li

  2. School of Nursing, Hebei Medical University, 309 Jianhua South Street, Shijiazhuang, 050000, People’s Republic of China

    Rui Jiang

  3. Central Laboratory, The Second Hospital of Hebei Medical University, 215 Heping West Road, Shijiazhuang, 050000, People’s Republic of China

    Li Li

  4. Department of Emergency Critical Care Medicine, The Second Hospital of Hebei Medical University, 215 Heping West Road, Shijiazhuang, 050000, People’s Republic of China

    Bu Wang

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  1. Rui Jiang
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Contributions

Wen-Bin Li and Rui Jiang conceived and designed the study. Bu Wang took care of animals and prepared them for experiments. Rui Jiang and Li Li performed the experiments. Xiao-Hui Xian assisted in electrophysiology experiments. Li-Zhe Liu and Li-Rong Liu analyzed the data. All authors read and approved the present version of the manuscript to be published.

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Correspondence to Xiaohui Xian or Wenbin Li.

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All animal experiments and the study protocols were approved by the Laboratory Animal Ethical and Welfare Committee of the Hebei Medical University, China (IACUC-Hebmu-2022013).

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Jiang, R., Li, L., Wang, B. et al. Ceftriaxone Modulates Ubiquitination of α-Amino-3-Hydroxy-5-Methyl-4-Isoxazole Propionic Acid Receptors to Improve Long-Term Potentiation Impairment Induced by Exogenous β-Amyloid in a Glutamate Transporter-1 Dependent Manner. Mol Neurobiol (2024). https://doi.org/10.1007/s12035-024-04037-3

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