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Thioredoxin-80 protects against amyloid-beta pathology through autophagic-lysosomal pathway regulation

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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References

  1. Nilsson P, Saido TC. Dual roles for autophagy: degradation and secretion of Alzheimer’s disease A beta peptide. Bioessays. 2014;36:570–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Akwa Y, Gondard E, Mann A, Capetillo-Zarate E, Alberdi E, Matute C, et al. Synaptic activity protects against AD and FTD-like pathology via autophagic-lysosomal degradation. Mol Psychiatry. 2017;23:1530–40.

    PubMed  PubMed Central  Google Scholar 

  3. Gerenu G, Martisova E, Ferrero H, Carracedo M, Rantamaki T, Ramirez MJ, et al. Modulation of BDNF cleavage by plasminogen-activator inhibitor-1 contributes to Alzheimer’s neuropathology and cognitive deficits. Biochim Biophys Acta. 2017;1863:991–1001.

    CAS  Google Scholar 

  4. Finder VH, Glockshuber R. Amyloid-beta aggregation. Neurodegener Dis. 2007;4:13–27.

    CAS  PubMed  Google Scholar 

  5. Epis R, Marcello E, Gardoni F, Di Luca M. Alpha, beta-and gamma-secretases in Alzheimer’s disease. Front Biosci (Sch Ed). 2012;4:1126–50.

    Google Scholar 

  6. Selkoe DJ. Alzheimer’s disease: genes, proteins, and therapy. Physiol Rev. 2001;81:741–66.

    CAS  PubMed  Google Scholar 

  7. Arner ES, Holmgren A. Physiological functions of thioredoxin and thioredoxin reductase. Eur J Biochem. 2000;267:6102–9.

    CAS  PubMed  Google Scholar 

  8. Pekkari K, Gurunath R, Arner ES, Holmgren A. Truncated thioredoxin is a mitogenic cytokine for resting human peripheral blood mononuclear cells and is present in human plasma. J Biol Chem. 2000;275:37474–80.

    CAS  PubMed  Google Scholar 

  9. King BC, Nowakowska J, Karsten CM, Kohl J, Renstrom E, Blom AM. Truncated and full-length thioredoxin-1 have opposing activating and inhibitory properties for human complement with relevance to endothelial surfaces. J Immunol. 2012;188:4103–12.

    CAS  PubMed  Google Scholar 

  10. Gil-Bea F, Akterin S, Persson T, Mateos L, Sandebring A, Avila-Carino J, et al. Thioredoxin-80 is a product of alpha-secretase cleavage that inhibits amyloid-beta aggregation and is decreased in Alzheimer’s disease brain. EMBO Mol Med. 2012;4:1097–111.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Hermansson E, Schultz S, Crowther D, Linse S, Winblad B, Westermark G, et al. The chaperone domain BRICHOS prevents CNS toxicity of amyloid-beta peptide in Drosophila melanogaster. Dis Model Mech. 2014;7:659–65.

    PubMed  PubMed Central  Google Scholar 

  12. Crowther DC, Kinghorn KJ, Miranda E, Page R, Curry JA, Duthie FA, et al. Intraneuronal Abeta, non-amyloid aggregates and neurodegeneration in a Drosophila model of Alzheimer’s disease. Neuroscience. 2005;132:123–35.

    CAS  PubMed  Google Scholar 

  13. Duffy JB. GAL4 system in Drosophila: a fly geneticist’s Swiss army knife. Genesis. 2002;34:1–15.

    CAS  PubMed  Google Scholar 

  14. Iwata N, Tsubuki S, Takaki Y, Shirotani K, Lu B, Gerard NP, et al. Metabolic regulation of brain Abeta by neprilysin. Science. 2001;292:1550–2.

    CAS  PubMed  Google Scholar 

  15. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 2001;25:402–8.

    CAS  PubMed  Google Scholar 

  16. Naslund J, Haroutunian V, Mohs R, Davis KL, Davies P, Greengard P, et al. Correlation between elevated levels of amyloid beta-peptide in the brain and cognitive decline. J Am Med Assoc. 2000;283:1571–7.

    CAS  Google Scholar 

  17. Zheng L, Calvo-Garrido J, Hallbeck M, Hultenby K, Marcusson J, Cedazo-Minguez A, et al. Intracellular localization of amyloid-beta peptide in SH-SY5Y neuroblastoma cells. J Alzheimers Dis. 2013;37:713–33.

    CAS  PubMed  Google Scholar 

  18. Ito K, Shinomiya K, Ito M, Armstrong JD, Boyan G, Hartenstein V, et al. A systematic nomenclature for the insect brain. Neuron. 2014;81:755–65.

    CAS  PubMed  Google Scholar 

  19. Poska H, Haslbeck M, Kurudenkandy FR, Hermansson E, Chen G, Kostallas G, et al. Dementia-related Bri2 BRICHOS is a versatile molecular chaperone that efficiently inhibits Abeta42 toxicity in Drosophila. Biochem J. 2016;473:3683–704.

    CAS  PubMed  Google Scholar 

  20. Mizushima N, Yoshimori T, Levine B. Methods in mammalian autophagy research. Cell. 2010;140:313–26.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Nixon RA. Autophagy, amyloidogenesis and Alzheimer disease. J Cell Sci. 2007;120(Pt 23):4081–91.

    CAS  PubMed  Google Scholar 

  22. Nakatogawa H, Ichimura Y, Ohsumi Y. Atg8, a ubiquitin-like protein required for autophagosome formation, mediates membrane tethering and hemifusion. Cell. 2007;130:165–78.

    CAS  PubMed  Google Scholar 

  23. Galluzzi L, Baehrecke EH, Ballabio A, Boya P, Bravo-San Pedro JM, Cecconi F, et al. Molecular definitions of autophagy and related processes. EMBO J. 2017;36:1811–36.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Ulgherait M, Rana A, Rera M, Graniel J, Walker DW. AMPK modulates tissue and organismal aging in a non-cell-autonomous manner. Cell Rep. 2014;8:1767–80.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Willows R, Sanders MJ, Xiao B, Patel BR, Martin SR, Read J, et al. Phosphorylation of AMPK by upstream kinases is required for activity in mammalian cells. Biochem J. 2017;474:3059–73.

    CAS  PubMed  Google Scholar 

  26. Freeman MR, Delrow J, Kim J, Johnson E, Doe CQ. Unwrapping glial biology: Gcm target genes regulating glial development, diversification, and function. Neuron. 2003;38:567–80.

    CAS  PubMed  Google Scholar 

  27. Logan MA, Hackett R, Doherty J, Sheehan A, Speese SD, Freeman MR. Negative regulation of glial engulfment activity by Draper terminates glial responses to axon injury. Nat Neurosci. 2012;15:722–30.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Rogeberg M, Furlund CB, Moe MK, Fladby T. Identification of peptide products from enzymatic degradation of amyloid beta. Biochimie. 2014;105:216–20.

    CAS  PubMed  Google Scholar 

  29. Caccamo A, Ferreira E, Branca C, Oddo S. p62 improves AD-like pathology by increasing autophagy. Mol Psychiatry. 2017;22:865–73.

    CAS  PubMed  Google Scholar 

  30. Hong L, Huang HC, Jiang ZF. Relationship between amyloid-beta and the ubiquitin-proteasome system in Alzheimer’s disease. Neurol Res. 2014;36:276–82.

    CAS  PubMed  Google Scholar 

  31. Kurochkin IV. Insulin-degrading enzyme: embarking on amyloid destruction. Trends Biochem Sci. 2001;26:421–5.

    CAS  PubMed  Google Scholar 

  32. Qiu WQ, Folstein MF. Insulin, insulin-degrading enzyme and amyloid-beta peptide in Alzheimer’s disease: review and hypothesis. Neurobiol Aging. 2006;27:190–8.

    CAS  PubMed  Google Scholar 

  33. Farris W, Schutz SG, Cirrito JR, Shankar GM, Sun X, George A, et al. Loss of neprilysin function promotes amyloid plaque formation and causes cerebral amyloid angiopathy. Am J Pathol. 2007;171:241–51.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Akterin S, Cowburn RF, Miranda-Vizuete A, Jimenez A, Bogdanovic N, Winblad B, et al. Involvement of glutaredoxin-1 and thioredoxin-1 in beta-amyloid toxicity and Alzheimer’s disease. Cell Death Differ. 2006;13:1454–65.

    CAS  PubMed  Google Scholar 

  35. Kaur J, Debnath J. Autophagy at the crossroads of catabolism and anabolism. Nat Rev Mol Cell Biol. 2015;16:461–72.

    CAS  PubMed  Google Scholar 

  36. Katsuragi Y, Ichimura Y, Komatsu M. p62/SQSTM1 functions as a signaling hub and an autophagy adaptor. FEBS J. 2015;282:4672–8.

    CAS  PubMed  Google Scholar 

  37. Pekkari K, Holmgren A. Truncated thioredoxin: physiological functions and mechanism. Antioxid Redox Signal. 2004;6:53–61.

    CAS  PubMed  Google Scholar 

  38. Couchie D, Vaisman B, Abderrazak A, Mahmood DFD, Hamza MM, Canesi F, et al. Human plasma thioredoxin-80 increases with age and in ApoE-/- mice induces inflammation, angiogenesis, and atherosclerosis. Circulation. 2017;136:464–75.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Kumar S, Rezaei-Ghaleh N, Terwel D, Thal DR, Richard M, Hoch M, et al. Extracellular phosphorylation of the amyloid beta-peptide promotes formation of toxic aggregates during the pathogenesis of Alzheimer’s disease. EMBO J. 2011;30:2255–65.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Ihara Y, Morishima-Kawashima M, Nixon R. The ubiquitin-proteasome system and the autophagic-lysosomal system in Alzheimer disease. Cold Spring Harb Perspect Med. 2012;2:1–28.

  41. Ciechanover A, Kwon YT. Degradation of misfolded proteins in neurodegenerative diseases: therapeutic targets and strategies. Exp Mol Med. 2015;47:e147.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Vilchez D, Saez I, Dillin A. The role of protein clearance mechanisms in organismal ageing and age-related diseases. Nat Commun. 2014;5:5659.

    CAS  PubMed  Google Scholar 

  43. Botti-Millet J, Nascimbeni AC, Dupont N, Morel E, Codogno P. Fine-tuning autophagy: from transcriptional to posttranslational regulation. Am J Physiol Cell Physiol. 2016;311:C351–62.

    PubMed  Google Scholar 

  44. Fullard JF, Baker NE. Signaling by the engulfment receptor draper: a screen in Drosophila melanogaster implicates cytoskeletal regulators, Jun N-terminal Kinase, and Yorkie. Genetics. 2015;199:117–34.

    CAS  PubMed  Google Scholar 

  45. McPhee CK, Balgley BM, Nelson C, Hill JH, Batlevi Y, Fang X, et al. Identification of factors that function in Drosophila salivary gland cell death during development using proteomics. Cell Death Differ. 2013;20:218–25.

    CAS  PubMed  Google Scholar 

  46. McPhee CK, Logan MA, Freeman MR, Baehrecke EH. Activation of autophagy during cell death requires the engulfment receptor Draper. Nature. 2010;465:1093–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Hailey DW, Rambold AS, Satpute-Krishnan P, Mitra K, Sougrat R, Kim PK, et al. Mitochondria supply membranes for autophagosome biogenesis during starvation. Cell. 2010;141:656–67.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Yoshimori T, Yamamoto A, Moriyama Y, Futai M, Tashiro Y. Bafilomycin A1, a specific inhibitor of vacuolar-type H(+)-ATPase, inhibits acidification and protein degradation in lysosomes of cultured cells. J Biol Chem. 1991;266:17707–12.

    CAS  PubMed  Google Scholar 

  49. Nixon RA, Yang DS. Autophagy failure in Alzheimer’s disease-locating the primary defect. Neurobiol Dis. 2011;43:38–45.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Nilsson P, Loganathan K, Sekiguchi M, Matsuba Y, Hui K, Tsubuki S, et al. Abeta secretion and plaque formation depend on autophagy. Cell Rep. 2013;5:61–69.

    CAS  PubMed  Google Scholar 

  51. Yu WH, Kumar A, Peterhoff C, Shapiro Kulnane L, Uchiyama Y, Lamb BT, et al. Autophagic vacuoles are enriched in amyloid precursor protein-secretase activities: implications for beta-amyloid peptide over-production and localization in Alzheimer’s disease. Int J Biochem Cell Biol. 2004;36:2531–40.

    CAS  PubMed  Google Scholar 

  52. Maxfield FR. Role of endosomes and lysosomes in human disease. Cold Spring Harb Perspect Biol. 2014;6:a016931.

    PubMed  PubMed Central  Google Scholar 

  53. Chan LL, Shen D, Wilkinson AR, Patton W, Lai N, Chan E, et al. A novel image-based cytometry method for autophagy detection in living cells. Autophagy. 2012;8:1371–82.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Riley BE, Kaiser SE, Shaler TA, Ng AC, Hara T, Hipp MS, et al. Ubiquitin accumulation in autophagy-deficient mice is dependent on the Nrf2-mediated stress response pathway: a potential role for protein aggregation in autophagic substrate selection. J Cell Biol. 2010;191:537–52.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Joshi G, Gan KA, Johnson DA, Johnson JA. Increased Alzheimer’s disease-like pathology in the APP/ PS1DeltaE9 mouse model lacking Nrf2 through modulation of autophagy. Neurobiol Aging. 2015;36:664–79.

    CAS  PubMed  Google Scholar 

  56. Cortes-Bratti X, Basseres E, Herrera-Rodriguez F, Botero-Kleiven S, Coppotelli G, Andersen JB, et al. Thioredoxin 80-activated-monocytes (TAMs) inhibit the replication of intracellular pathogens. PLoS ONE. 2011;6:e16960.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Perez-Perez ME, Zaffagnini M, Marchand CH, Crespo JL, Lemaire SD. The yeast autophagy protease Atg4 is regulated by thioredoxin. Autophagy. 2014;10:1953–64.

    PubMed  PubMed Central  Google Scholar 

  58. Munoz-Lobato F, Rodriguez-Palero MJ, Naranjo-Galindo FJ, Shephard F, Gaffney CJ, Szewczyk NJ, et al. Protective role of DNJ-27/ERdj5 in Caenorhabditis elegans models of human neurodegenerative diseases. Antioxid Redox Signal. 2014;20:217–35.

    CAS  PubMed  PubMed Central  Google Scholar 

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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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Correspondence to Gorka Gerenu or Angel Cedazo-Minguez.

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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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