Levosimendan prevents tau pathology by inhibiting disulfide-linked tau oligomerization posing as a promising anti-tau therapeutics

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 have developed a tau-BiFC platform to monitor and quantify tau oligomerization. By using the tau-BiFC platform, we screened 1,018 compounds in FDA-approved & Passed Phase I 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, and rescuing neurons from aggregation states. In comparison, the well-known anti-tau agents, methylene blue (MB) and LMTM, failed to protect neurons from tau-mediated toxicity, generating high-molecular weight tau oligomers. The administration of levosimendan also suppressed tau pathology in the brain, preventing cognitive declines in TauP301L-BiFC transgenic mice. Although careful validation is required, here we present the potential of levosimendan as a disease modifying therapy for tauopathies targeting tau oligomerization.