Levosimendan inhibits disulfide tau oligomerization ameliorating tau pathology in TauP301L-BiFC mice

Abstract

Abstract Tau oligomers play critical roles in tau pathology, responsible for neuronal cell death and transmitting the disease in the brain. Accordingly, preventing tau oligomerization becomes an important therapeutic strategy to treat tauopathies including Alzheimer’s disease. However, progress has been slow due to difficulties of detecting tau oligomers in cellular context. Toward tau-targeted drug discovery, our group has developed a tau-BiFC platform to monitor and quantify tau oligomerization. By using the tau-BiFC platform, we screened FDA-approved & Passed PhaseI drug library, and identified levosimendan as a potent anti-tau agent inhibiting tau oligomerization. 14C-isotope labeling of levosimendan identified that levosimendan covalently bound to tau cysteines, directly inhibiting disulfide-linked tau oligomerization. In addition, levosimendan was able to disassemble tau oligomers into monomers, rescuing neurons from aggregation states. In comparison, the well-known anti-tau agents, methylene blue and LMTM, failed to protect neurons from tau-mediated toxicity, generating high-molecular-weight tau oligomers. Levosimendan displayed robust potency against tau oligomerization and rescued tauopathy-induced cognitive declines in TauP301L-BiFC mouse model. Our data present the potential of levosimendan as a disease-modifying drug for tauopathies.