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- Title
A prolyl oligopeptidase inhibitor reduces tau pathology in cellular models and in mice with tauopathy.
- Authors
Eteläinen, Tony S.; Silva, M. Catarina; Uhari-Väänänen, Johanna K.; De Lorenzo, Francesca; Jäntti, Maria H.; Cui, Hengjing; Chavero-Pieres, Marta; Kilpeläinen, Tommi; Mechtler, Christina; Svarcbahs, Reinis; Seppälä, Erin; Savinainen, Juha R.; Puris, Elena; Fricker, Gert; Gynther, Mikko; Julku, Ulrika H.; Huttunen, Henri J.; Haggarty, Stephen J.; Myöhänen, Timo T.
- 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. Prolyl oligopeptidase inhibition to tackle tau aggregation: Decreased protein phosphatase 2A (PP2A) activity contributes to the accumulation of hyperphosphorylated tau protein and the formation of tau aggregates in neurodegenerative tauopathies. The serine protease prolyl oligopeptidase colocalizes with tau, and its inhibition normalizes PP2A activity in models of Alzheimer's disease. Eteläinen et al. used several cell models of tauopathy to demonstrate that the prolyl oligopeptidase inhibitor KYP-2047 reduced tau aggregation by increasing PP2A activity and by enhancing autophagic flux. Furthermore, KYP-2047 ameliorated cognitive dysfunction and tau accumulation in the PS19 mouse model of tauopathy, suggesting that prolyl oligopeptidase inhibition could be a potential therapeutic strategy for tauopathies. —DN
- Subjects
TAU proteins; TAUOPATHIES; CELLULAR pathology; ALZHEIMER'S disease; ANIMAL disease models; PHOSPHOPROTEIN phosphatases
- Publication
Science Translational Medicine, 2023, Vol 15, Issue 691, p1
- ISSN
1946-6234
- Publication type
Article
- DOI
10.1126/scitranslmed.abq2915