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Differential dysregulation of CREB and synaptic genes in transgenic Drosophila melanogaster expressing shaggy (GSK3), TauWT, or Amyloid-beta

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Abstract

Background

Tau, Amyloid-beta (Aβ42), and Glycogen synthase kinase 3 (GSK3) contribute to synaptic dysfunction observed in Alzheimer's disease (AD), the most common form of dementia. In the current study, the effect of pan-neuronal expression of TauWT, Aβ42, or shaggy (orthologue of GSK3) in Drosophila melanogaster was assessed on the locomotor function, ethanol sensitivity, synaptic genes and CREB expression. The effect of TauWT and Aβ42 on the expression of shaggy was also determined.

Methods and results

Gene expression analysis was performed using quantitative real-time RT-PCR method. While syt1, SNAP25 and CREB (upstream transcription factor of syt1 and SNAP25) were upregulated in flies expressing TauWT or Aβ42, a prominent decline was observed in those genes in shaggy expressing flies. Although all transgenic flies showed climbing disability and higher sensitivity to ethanol, abnormality in these features was significantly more prominent in transgenic flies expressing shaggy compared to TauWT or Aβ42. Despite a significant upregulation of shaggy transcription in TauWT expressing flies, Aβ42 transgenic flies witnessed no significant changes.

Conclusions

TauWT, Aβ42, and shaggy may affect synaptic plasticity through dysregulation of synaptic genes and CREB, independently. However shaggy has more detrimental effect on synaptic genes expression, locomotor ability and sensitivity to ethanol. It is important when it comes to drug discovery. It appears that CREB is a direct effector of changes in synaptic genes expression as they showed similar pattern of alteration and it is likely to be a part of compensatory mechanisms independent of the GSK3/CREB pathway in TauWT or Aβ42 expressing flies.

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Acknowledgements

This work was financially supported by a research grant from Shiraz University. The authors would like to thank Amir-Hussein Hadaegh (Central Laboratory of Shiraz University of Medical Sciences) for his assistance and helpful comments.

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Authors and Affiliations

  1. Department of Biology, College of Sciences, Shiraz University, Shiraz, Iran

    Fatemeh Ataellahi & Raheleh Masoudi

  2. Department of Biology, Faculty of Basic Sciences, University of Zabol, Zabol, Iran

    Mohammad Haddadi

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Contributions

RM, conceived the presented idea, designed the experiments, contributed to the interpretation of the results and writing the manuscript. FA, performed the molecular and behavioral experiments and their statistical analysis and interpretation, wrote the manuscript and contributed to the conception of the idea. MH, guided and helped to design the experiments related to flies and provided the Drosophila stocks.

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Correspondence to Raheleh Masoudi.

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Drosophila experiments do not require ethics committee approval. However, all expreriments were conducted ethically and the number of animals used as kept to a minimum.

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Ataellahi, F., Masoudi, R. & Haddadi, M. Differential dysregulation of CREB and synaptic genes in transgenic Drosophila melanogaster expressing shaggy (GSK3), TauWT, or Amyloid-beta. Mol Biol Rep 50, 1101–1108 (2023). https://doi.org/10.1007/s11033-022-08059-9

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