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A prolyl oligopeptidase inhibitor reduces tau pathology in cellular models and in mice with tauopathy

Tauopathies are neurodegenerative diseases that are characterized by accumulation of hyperphosphorylated tau protein, higher-order aggregates, and tau filaments. Protein phosphatase 2A (PP2A) is a major tau dephosphorylating phosphatase, and a decrease in its activity has been demonstrated in tauopa...

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Main Authors: Eteläinen, Tony (Author) , Silva, M. Catarina (Author) , Uhari-Väänänen, Johanna K. (Author) , De Lorenzo, Francesca (Author) , Jäntti, Maria H. (Author) , Cui, Hengjing (Author) , Chavero-Pieres, Marta (Author) , Kilpeläinen, Tommi (Author) , Mechtler, Christina (Author) , Svarcbahs, Reinis (Author) , Seppälä, Erin (Author) , Savinainen, Juha R. (Author) , Puris, Elena (Author) , Fricker, Gert (Author) , Gynther, Mikko (Author) , Julku, Ulrika H. (Author) , Huttunen, Henri J. (Author) , Haggarty, Stephen J. (Author) , Myöhänen, Timo T. (Author)
Format: Article (Journal)
Language:English
Published: 12 Apr 2023
In: Science translational medicine
Year: 2023, Volume: 15, Issue: 691, Pages: 1-17
ISSN:1946-6242
DOI:10.1126/scitranslmed.abq2915
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1126/scitranslmed.abq2915
Verlag, lizenzpflichtig, Volltext: https://www.science.org/doi/10.1126/scitranslmed.abq2915
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Author Notes:Tony S. Eteläinen, M. Catarina Silva, Johanna K. Uhari-Väänänen, Francesca De Lorenzo, Maria H. Jäntti, Hengjing Cui, Marta Chavero-Pieres, Tommi Kilpeläinen, Christina Mechtler, Reinis Svarcbahs, Erin Seppälä, Juha R. Savinainen, Elena Puris, Gert Fricker, Mikko Gynther, Ulrika H. Julku, Henri J. Huttunen, Stephen J. Haggarty, Timo T. Myöhänen
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Summary:Tauopathies are neurodegenerative diseases that are characterized by accumulation of hyperphosphorylated tau protein, higher-order aggregates, and tau filaments. Protein phosphatase 2A (PP2A) is a major tau dephosphorylating phosphatase, and a decrease in its activity has been demonstrated in tauopathies, including Alzheimer’s disease. Prolyl oligopeptidase is a serine protease that is associated with neurodegeneration, and its inhibition normalizes PP2A activity without toxicity under pathological conditions. Here, we assessed whether prolyl oligopeptidase inhibition could protect against tau-mediated toxicity in cellular models in vitro and in the PS19 transgenic mouse model of tauopathy carrying the human tau-P301S mutation. We show that inhibition of prolyl oligopeptidase with the inhibitor KYP-2047 reduced tau aggregation in tau-transfected HEK-293 cells and N2A cells as well as in human iPSC-derived neurons carrying either the P301L or tau-A152T mutation. Treatment with KYP-2047 resulted in increased PP2A activity and activation of autophagic flux in HEK-293 cells and N2A cells and in patient-derived iNeurons, as indicated by changes in autophagosome and autophagy receptor markers; this contributed to clearance of insoluble tau. Furthermore, treatment of PS19 transgenic mice for 1 month with KYP-2047 reduced tau burden in the brain and cerebrospinal fluid and slowed cognitive decline according to several behavioral tests. In addition, a reduction in an oxidative stress marker was seen in mouse brains after KYP-2047 treatment. This study suggests that inhibition of prolyl oligopeptidase could help to ameliorate tau-dependent neurodegeneration.
Item Description:Gesehen am 05.07.2023
Physical Description:Online Resource
ISSN:1946-6242
DOI:10.1126/scitranslmed.abq2915

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