Stimulation of plasmin activity by acetylsalicylic acid hinders prion propagation in vitro and in vivo

Autocatalytic propagation of PrP Sc , the misfolded isoform of the cellular prion protein (PrP C ), is the hallmark of fatal, neurodegenerative disorders termed prion diseases. Physiologically, PrP C undergoes α-cleavage, generating C1 and N1 fragments, which disrupts the region necessary for conversion of PrP C to PrP Sc . Recently, we reported that plasmin, an enzyme that cleaves PrP C at the α-site, substantially inhibits PrP conversion and prion propagation. Here, we investigated whether stimulation of plasmin activity by acetylsalicylic acid (ASA) would enhance α-cleavage of PrP C and suppression of prion propagation in vitro and in vivo. ASA stimulated plasmin to induce α-cleavage of recombinant PrP, preventing its aggregation, in PrP cleavage and PrP self-aggregation assays. ASA enhanced plasmin-mediated suppression of PrP Sc propagation in protein misfolding cyclic amplification. Furthermore, ASA significantly enhanced endogenous plasmin activity, increased C1 fragment generation, and reduced the PrP Sc level in both prion-infected cultured cells and mouse brains. These events were translated to the reduction of prion infectivity in standard scrapie cell assay. In addition, ASA prolonged incubation time, prevented disease-associated neuropathology, and attenuated the reduction of synaptic marker proteins in a mouse model of prion disease. Our findings demonstrate that ASA-mediated activation of plasmin promotes α-cleavage of PrP C , hindering prion replication and disease progression in vitro and in vivo. These results suggest that prion suppression is feasible by control of plasmin activity associated with cellular processing of PrP C and propose a potential therapeutic target for prion diseases.