Abstract
Aggregation and accumulation of amyloid beta (Aβ) are believed to play a key role in the pathogenesis of Alzheimer’s disease (AD). We previously reported that Thioredoxin-80 (Trx80), a truncated form of Thioredoxin-1, prevents the toxic effects of Aβ and inhibits its aggregation in vitro. Trx80 levels were found to be dramatically reduced both in the human brain and cerebrospinal fluid of AD patients. In this study, we investigated the effect of Trx80 expression using in vivo and in vitro models of Aβ pathology. We developed Drosophila melanogaster models overexpressing either human Trx80, human Aβ42, or both Aβ42/Trx80 in the central nervous system. We found that Trx80 expression prevents Aβ42 accumulation in the brain and rescues the reduction in life span and locomotor impairments seen in Aβ42 expressing flies. Also, we show that Trx80 induces autophagosome formation and reverses the inhibition of Atg4b-Atg8a/b autophagosome formation pathway caused by Aβ42. These effects were also confirmed in human neuroblastoma cells. These results give insight into Trx80 function in vivo, suggesting its role in the autophagosome biogenesis and thus in Aβ42 degradation. Our findings put Trx80 on the spotlight as an endogenous agent against Aβ42-induced toxicity in the brain suggesting that strategies to enhance Trx80 levels in neurons could potentially be beneficial against AD pathology in humans.
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Acknowledgements
We would like to acknowledge Janne Johansson for provide us the facilities of their lab and Gunnila Westermark for provide us the Aβ42 overexpressing flies. This study was partially performed at the Live Cell Imaging facility of Karolinska Institutet, (Sweden).
Funding
GGL was the recipient of the Basque Government Postdoctoral Fellowship (POS 2015-1-0028). This research was supported by the following Swedish foundations: HP was supported by The Swedish Institute Visby Program and European Social Fund’s Doctoral Studies and Internationalization Programme DoRa carried out by Archimedes Foundation. Swedish Brain Power, the regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska Institutet, Margaretha af Ugglas Foundation, Olle Engkvist Byggmästare Stiftelse, Gun och Bertil Stohnes Stiftelse, Loo och Hans Osterman Foundation, Karolinska Institutet fund for geriatric research, Stiftelsen Gamla Tjänarinnor, Alzheimerfonden, the Centre for Innovative Medicine and the Jonasson center at the Royal Institute of Technology (Sweden).
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GGL performed the most Drosophila animal model experiments as well as the majority of in vitro experiments. He wrote the manuscript together with TP and ACM, collecting input from all the authors. Together with ACM and TP, he planned the experiments and analyzed the results. TP collaborated in the creation of Drosophila models and performed several experiments including behavioral studies. He participated also in the writing process of the manuscript. JG participated in amyloid beta 42 measurements both in in vivo and in vitro models. He also participated in behavioral assays and the editing of the manuscript. JCG performed some of the in vitro experiments and participated in editing the paper. RLV participated in establishing the PCR array for the flies. Contributed to discuss results and interpretation of data. He revised the manuscript for consistency and grammar. PP participated in ELISAs measurements of Trx80 and Amyloid Beta 42. He has also contributed in writing the manuscript. CS and JP participated in the interpretation of the data as well as in the critical analysis of the results. HP helped in generating the Drosophila models and participated on the edition the paper. AC-M is the PI of the study. He reviewed and interpreted the results, led discussions to guide the paper scientifically and participated in the writing of manuscript.
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AC-M is currently working in Sanofi but declares no conflict of interest. The other authors have no conflict of interest to declare.
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Gerenu, G., Persson, T., Goikolea, J. et al. Thioredoxin-80 protects against amyloid-beta pathology through autophagic-lysosomal pathway regulation. Mol Psychiatry 26, 1410–1423 (2021). https://doi.org/10.1038/s41380-019-0521-2
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DOI: https://doi.org/10.1038/s41380-019-0521-2
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