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

• Verfasst von: Eteläinen, Tony [VerfasserIn]
• Verfasst von: Silva, M. Catarina [VerfasserIn]
• Verfasst von: Uhari-Väänänen, Johanna K. [VerfasserIn]
• Verfasst von: De Lorenzo, Francesca [VerfasserIn]
• Verfasst von: Jäntti, Maria H. [VerfasserIn]
• Verfasst von: Cui, Hengjing [VerfasserIn]
• Verfasst von: Chavero-Pieres, Marta [VerfasserIn]
• Verfasst von: Kilpeläinen, Tommi [VerfasserIn]
• Verfasst von: Mechtler, Christina [VerfasserIn]
• Verfasst von: Svarcbahs, Reinis [VerfasserIn]
• Verfasst von: Seppälä, Erin [VerfasserIn]
• Verfasst von: Savinainen, Juha R. [VerfasserIn]
• Verfasst von: Puris, Elena [VerfasserIn]
• Verfasst von: Fricker, Gert [VerfasserIn]
• Verfasst von: Gynther, Mikko [VerfasserIn]
• Verfasst von: Julku, Ulrika H. [VerfasserIn]
• Verfasst von: Huttunen, Henri J. [VerfasserIn]
• Verfasst von: Haggarty, Stephen J. [VerfasserIn]
• Verfasst von: Myöhänen, Timo T. [VerfasserIn]
• Titel: A prolyl oligopeptidase inhibitor reduces tau pathology in cellular models and in mice with tauopathy
• Verf.angabe: 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
• E-Jahr: 2023
• Jahr: 12 Apr 2023
• Umfang: 17 S.
• Fussnoten: Gesehen am 05.07.2023
• Titel Quelle: Enthalten in: Science translational medicine
• Ort Quelle: Washington, DC : AAAS, 2009
• Jahr Quelle: 2023
• Band/Heft Quelle: 15(2023), 691 vom: Apr., Artikel-ID eabq2915, Seite 1-17
• ISSN Quelle: 1946-6242
• DOI: doi:10.1126/scitranslmed.abq2915
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1851793267

Abstract

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.