Interaction of prolyl oligopeptidase (PREP) and tau - PREP as a drug target for treating tauopathies

抄録

Hyperphosphorylation of tau is a common problem in neurodegenerative diseases called Tauopathies, from which it is best established in Alzheimer's disease (AD). The current treatments for AD have no effect on the phosphorylation of tau and they are purely symptomatic. Reducing tau phosphorylation could provide a disease-modifying therapy to treat AD and other neurodegenerative diseases. In this study, we assessed the effect of small-molecule inhibitors of prolyl oligopeptidase (PREP) and PREP knock-down on okadaic acid induced phosphorylation of tau in several sites (S409, S262 and T205) in HEK-293 cells transiently overexpressing tau. PREP inhibitor (KYP-2047) decreased phosphorylation of S262 in HEK293 cells and HEK293-PREP KO cells showed decreased response to okadaic acid, a protein phosphatase 2A (PP2A) inhibitor, as seen by reduced phosphorylation of S409, when compared to control HEK-293 cells. We have recently shown that PREP inhibition activates PP2A but to study further the mechanism of how this reduced phosphorylation or increased dephosphorylation takes place, we investigated the direct interaction between PREP and tau. Utilizing protein complementation assay (PCA), we were able to show that PREP and tau do interact. This is similar to our previous finding with PREP and alpha-synuclein, the aggregating protein in Parkinson's disease. Furthermore, by utilizing different truncates of tau, we were able to determine that the interaction takes place in N-terminal side of Tau. Our results support the idea that PREP inhibitors could be potential drug candidates for disease-modifying treatment of AD.