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HIF-1α is a “brake” in JNK-mediated activation of amyloid protein precursor and hyperphosphorylation of tau induced by T-2 toxin in BV2 cells

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Abstract

Mycotoxins have been shown to activate multiple mechanisms that may potentially lead to the progression of Alzheimer’s disease (AD). Overexpression/aberrant cleavage of amyloid precursor protein (APP) and hyperphosphorylation of tau (P-tau) is hallmark pathologies of AD. Recent advances suggest that the neurotoxic effects of mycotoxins involve c-Jun N-terminal kinase (JNK) and hypoxia-inducible factor-1α (HIF-1α) signaling, which are closely linked to the pathogenesis of AD. Due to the high toxicity and broad contamination of T-2 toxin, we assessed how T-2 toxin exposure alters APP and P-tau formation in BV2 cells and determined the underlying roles of HIF-1α and JNK signaling. The findings revealed that T-2 toxin stimulated the expression of HIF-1α and hypoxic stress factors in addition to increasing the expression of APP and P-tau. Additionally, HIF-1α acted as a “brake” on the induction of APP and P-tau expression by negatively regulating these proteins. Notably, T-2 toxin activated JNK signaling, which broke this “brake” to promote the formation of APP and P-tau. Furthermore, the cytoskeleton was an essential target for T-2 toxin to exert cytotoxicity, and JNK/HIF-1α participated in this damage. Collectively, when the T-2 toxin induces the production of APP and P-tau, JNK might interfere with HIF-1α’s protective function. This study will provide clues for further research on the neurotoxicity of mycotoxins.

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Acknowledgements

We would like to thank the National Natural Science Foundation of China.

Funding

This work was supported by the National Natural Science Foundation of China (Grant nos. 31972741, 32373073, 32072925), MH CZ-DRO (UHHK, 00179906), Research Program of University of Granada, by the Charles University in Prague, Czechia (PROGRES Q40/15), and the Excellence Project PrF UHK 2217/2022-2023 Czech Republic.

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Authors and Affiliations

  1. College of Life Science, Yangtze University, Jingzhou, 434025, China

    Yingying Zhao & Qinghua Wu

  2. Department of Neurology, Charles University in Prague, Faculty of Medicine in Hradec Kralove and University Hospital, Hradec Králové, Czech Republic

    Martin Valis

  3. National Reference Laboratory of Veterinary Drug Residues and MAO Key Laboratory for Detection of Veterinary Drug Residues, Huazhong Agricultural University (HZAU), Wuhan, Hubei, 430070, China

    Xu Wang

  4. Department of Chemistry, Faculty of Science, University of Hradec Králové, 50003, Hradec Králové, Czech Republic

    Eugenie Nepovimova, Qinghua Wu & Kamil Kuca

  5. Andalusian Research Institute in Data Science and Computational Intelligence (DaSCI), University of Granada, 18071, Granada, Spain

    Kamil Kuca

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  1. Yingying Zhao
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  2. Martin Valis
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  3. Xu Wang
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  4. Eugenie Nepovimova
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Contributions

Yingying Zhao performed the experiment and drafted the manuscript. Martin Valis reviewed and analyzed the data. Xu Wang and Eugenie Nepovimova contributed to the discussion and review of the manuscript. Qinghua Wu and Kamil Kuca designed the research and analyzed the data. All co-authors reviewed and edited the manuscript and approved the submission.

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Zhao, Y., Valis, M., Wang, X. et al. HIF-1α is a “brake” in JNK-mediated activation of amyloid protein precursor and hyperphosphorylation of tau induced by T-2 toxin in BV2 cells. Mycotoxin Res 40, 223–234 (2024). https://doi.org/10.1007/s12550-024-00525-6

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