Cilostazol, a phosphodiesterase 3 inhibitor, activates proteasome-mediated proteolysis and attenuates tauopathy and cognitive decline.

Alzheimer's disease and several variants of frontotemporal degeneration including progressive supranuclear palsy and corticobasal degeneration are characterized by the accumulation of abnormal tau protein into aggregates. Most proteins, including tau, are degraded via the ubiquitin proteasome system, but when abnormal tau accumulates, the function of 26S proteasomes is downregulated. The negative effect of tau aggregates on the function of the proteasome can have deleterious consequences on protein homeostasis and disease progression. Developing therapies aimed at clearing abnormal tau are thus of considerable interest. In the present study, we investigated the effect of cilostazol, an FDA-approved selective phosphodiesterase 3 inhibitor, on a mouse model of tauopathy (line rTg4510). Administration of cilostazol for 30 days enhanced proteasome function via the cyclic adenosine 3',5'-monophosphate/protein kinase A pathway and attenuated tauopathy and cognitive decline in rTg4510 mice. These results suggest that cilostazol, or other FDA-approved drugs acting via the same pathway, has the potential to be repurposed for the treatment of patients with early-stage tauopathy.