Abstract
Glycogen synthase kinase 3β (GSK3β) is considered an important element of glycogen metabolism; however, it has many other regulatory roles. Changes in the GSK3β signaling mechanism have been associated with various disorders, such as Alzheimer’s disease (AD), type II diabetes, and cancer. Although the effects of GSK3β inhibitors on reducing the pathological effects of AD have been described, an effective inhibitor has not yet been developed. Epibrassinolide (EBR), a brassinosteroid (BR), is structurally similar to mammalian steroid hormones. Our studies have shown that EBR has an inhibitory effect on GSK3β in different cell lines. Roscovitine (ROSC), a cyclin-dependent kinase (CDK) inhibitor, has also been identified as a potential GSK3 inhibitor. Within the scope of this study, we propose that EBR and/or ROSC might have mechanistic action in AD models. To test this hypothesis, we used in vitro models and Caenorhabditis elegans (C. elegans) AD strains. Finally, EBR treatment successfully protected cells from apoptosis and increased the inhibitory phosphorylation of GSK3β. In addition, EBR and/or ROSC treatment had a positive effect on the survival rates of C. elegans strains. More interestingly, the paralysis phenotype of the C. elegans AD model due to Aβ42 toxicity was prevented by EBR and/or ROSC. Our findings suggest that EBR and ROSC administration have neuroprotective effects on both in vitro and C. elegans models via inhibitory GSK3β phosphorylation at Ser9.
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The data that support the findings of this study are available from the corresponding author, POY, upon reasonable request.
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Acknowledgements
This work was funded by The European Cooperation in Science and Technology (COST; project call, BM1408) and The Scientific and Technological Research Council of Turkey (TUBITAK; project number, 115Z037). We are thankful to Kaan Adacan, Mert Meseli, Resul İsmail Kaya, Cigdem Fidan, and Yagmur Yazla for technical assistance for Figs. 4a, b; 5a–d. We are also thankful to Börtecine Sevgin and Merve Nur Coban for ImageJ analyses.
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POY, EDA, and ACG conceived and planned the experiments and contributed to the interpretation of the results. POY wrote and EDA, ACG, and NPU reviewed and edited the original draft. OOO, TY, UO, and MK carried out the experiments.
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Obakan Yerlikaya, P., Arısan, E.D., Coker Gurkan, A. et al. Epibrassinolide prevents tau hyperphosphorylation via GSK3β inhibition in vitro and improves Caenorhabditis elegans lifespan and motor deficits in combination with roscovitine. Amino Acids 53, 1373–1389 (2021). https://doi.org/10.1007/s00726-021-03027-2
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DOI: https://doi.org/10.1007/s00726-021-03027-2