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TAT-W61 peptide attenuates neuronal injury through blocking the binding of S100b to the V-domain of Rage during ischemic stroke

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Abstract

Ischemic stroke is a devastative nervous system disease associated with high mortality and morbidity rates. Unfortunately, no clinically effective neuroprotective drugs are available now. In ischemic stroke, S100 calcium-binding protein b (S100b) binds to receptor for advanced glycation end products (Rage), leading to the neurological injury. Therefore, disruption of the interaction between S100B and Rage can rescue neuronal cells. Here, we designed a peptide, termed TAT-W61, derived from the V domain of Rage which can recognize S100b. Intriguingly, TAT-W61 can reduce the inflammatory caused by ischemic stroke through the direct binding to S100b. The further investigation demonstrated that TAT-W61 can improve pathological infarct volume and reduce the apoptotic rate. Particularly, TAT-W61 significantly improved the learning ability, memory, and motor dysfunction of the mouse in the ischemic stroke model. Our study provides a mechanistic insight into the abnormal expression of S100b and Rage in ischemic stroke and yields an invaluable candidate for the development of drugs in tackling ischemic stroke.

Key messages

  • S100b expression is higher in ischemic stroke, in association with a high expression of many genes, especially of Rage.

  • S100b is directly bound to the V-domain of Rage.

  • Blocking the binding of S100b to Rage improves the injury after ischemic stroke.

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Availability of data and materials

The data and materials in the current study are available from the corresponding author on reasonable request.

Abbreviations

MCAO:

Middle cerebral artery occlusion

I/R:

Ischemia/reperfusion

S100b:

S100 calcium binding protein b

Rage:

Receptor of advanced glycation end products

TTC:

2,3,5-Triphenyltetrazolium chloride

OGD/R:

Oxygen glucose deprivation/reperfusion

MWM:

Morris water maze

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Funding

This work was supported by the Jiangsu Province Innovative and Entrepreneurial Team Program, the Six Talent Peaks Project in Jiangsu Province (WSN-089), Development Fund of The Affiliated Hospital of Xuzhou Medical University in 2021(XYFM2021010), the National Natural Science Foundation of China (82104150), and Foundation of Xuzhou Medical University (D2018004). We are grateful to all the staff in the Jiangsu Province Key Laboratory of Anesthesiology, Public Experimental Research Center and Experimental Animal Center of Xuzhou Medical University, for their support and help during the experiments.

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Authors and Affiliations

  1. Xuzhou Engineering Research Center of Medical Genetics and Transformation, Key Laboratory of Genetic Foundation and Clinical Application, Department of Genetics, Xuzhou Medical University, Xuzhou, 221004, China

    Jia Liang, Hui Li, Xiao‑Yan Zhou, Xiang-Yu Ma, Dan Liu, Yu-Ling Chen, Qian Feng, Zhen Zhang & Yuan-Jian Song

  2. Department of Pathology, Xuzhou Medical University, Xuzhou, 221004, China

    Jia Liang

  3. State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong SAR, 00000, China

    Chang‑Dong Liu & Guang Zhu

  4. Department of Cell Biology and Neurobiology, Xuzhou Medical University, Xuzhou, 221004, China

    Yan‑Yan Fu

  5. Department of Chemistry, School of Pharmacy, Xuzhou Medical University, Xuzhou, 221004, China

    Xiang-Ru Wen

  6. Research Center for Biochemistry and Molecular Biology, Jiangsu Key Laboratory of Brain Disease Bioinformation, Xuzhou 221004, Jiangsu, China

    Nan Wang & Yuan-Jian Song

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  1. Jia Liang
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Contributions

YJS and NW initiated and designed the project; JL performed the main experiments, analyzed experimental results, and drafted the article; HL and NW performed bioinformatics analysis and structure analysis. XYM and DL took part in western blot. YLC, QF, and ZZ performed behavioral experiments. XRW took part in immunohistochemistry. All the authors read and approved the final manuscript.

Corresponding authors

Correspondence to Nan Wang or Yuan-Jian Song.

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The project “TAT-W61 peptide attenuates neuronal injury through blocking the binding of S100b to the V-domain of Rage during ischemic stroke” was examined and verified by Laboratory Animal Ethics Committee of Xuzhou Medical University in accordance with Guide to Laboratory Animal Ethics Examination of Xuzhou Medical University (201907A008). And relative animal experiments are permitted.

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Liang, J., Li, H., Liu, C. et al. TAT-W61 peptide attenuates neuronal injury through blocking the binding of S100b to the V-domain of Rage during ischemic stroke. J Mol Med 102, 231–245 (2024). https://doi.org/10.1007/s00109-023-02402-8

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  • DOI: https://doi.org/10.1007/s00109-023-02402-8

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