Levosimendan inhibits disulfide tau oligomerization and ameliorates tau pathology in TauP301L-BiFC mice
Sungsu Lim, Seulgi Shin, Yoonsik Sung, Ha Eun Lee, Kyu Hyeon Kim, Ji Yeon Song, Gwan‐Ho Lee, Hira Aziz, Nataliia Lukianenko, Dong Min Kang, Nicolette Boesen, Hyeanjeong Jeong, Aizhan Abdildinova, Junghee Lee, Byung Yong Yu, Sang Min Lim, Jun‐Seok Lee, Hoon Ryu, Ae Nim Pae, Yun Kyung Kim
Abstract
Abstract Tau oligomers play critical roles in tau pathology and are responsible for neuronal cell death and transmitting the disease in the brain. Accordingly, preventing tau oligomerization has become an important therapeutic strategy to treat tauopathies, including Alzheimer’s disease. However, progress has been slow because detecting tau oligomers in the cellular context is difficult. Working 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 libraries with FDA-approved and passed phase I drugs and identified levosimendan as a potent anti-tau agent that inhibits tau oligomerization. 14 C-isotope labeling of levosimendan revealed that levosimendan covalently bound to tau cysteines, directly inhibiting disulfide-linked tau oligomerization. In addition, levosimendan disassembles 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 cognitive declines induced by tauopathy in the Tau P301L -BiFC mouse model. Our data present the potential of levosimendan as a disease-modifying drug for tauopathies.