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 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.

Removal of proteinase K resistant αSyn species does not correlate with cell survival in a virus vector-based Parkinson's disease mouse model.

Parkinson's disease (PD) is characterized by degeneration of nigrostriatal dopaminergic neurons and accumulation of α-synuclein (αSyn) as Lewy bodies. Currently, there is no disease-modifying therapy available for PD. We have shown that a small molecular inhibitor for prolyl oligopeptidase (PREP), KYP-2047, relieves αSyn-induced toxicity in various PD models by inducing autophagy and preventing αSyn aggregation. In this study, we wanted to study the effects of PREP inhibition on different αSyn species by using cell culture and in vivo models. We used Neuro2A cells with transient αSyn overexpression and oxidative stress or proteasomal inhibition-induced αSyn aggregation to assess the effect of KYP-2047 on soluble αSyn oligomers and on cell viability. Here, the levels of soluble αSyn were measured by using ELISA, and the impact of KYP-2047 was compared to anle138b, nilotinib and deferiprone. To evaluate the effect of KYP-2047 on αSyn fibrillization in vivo, we used unilateral nigral AAV1/2-A53T-αSyn mouse model, where the KYP-2047 treatment was initiated two- or four-weeks post injection. KYP-2047 and anle138b protected cells from αSyn toxicity but interestingly, KYP-2047 did not reduce soluble αSyn oligomers. In AAV-A53T-αSyn mouse model, KYP-2047 reduced significantly proteinase K-resistant αSyn oligomers and oxidative damage related to αSyn aggregation. However, the KYP-2047 treatment that was initiated at the time of symptom onset, failed to protect the nigrostriatal dopaminergic neurons. Our results emphasize the importance of whole αSyn aggregation process in the pathology of PD and raise an important question about the forms of αSyn that are reasonable targets for PD drug therapy.