한빛사논문
Sungsu Lim1,8, Seulgi Shin1,8, Yoonsik Sung1,2, Ha Eun Lee1, Kyu Hyeon Kim1,2, Ji Yeon Song1, Gwan-Ho Lee3, Hira Aziz1,2, Nataliia Lukianenko1,2, Dong Min Kang1,4, Nicolette Boesen1,2, Hyeanjeong Jeong1, Aizhan Abdildinova1, Junghee Lee5, Byung-Yong Yu3, Sang Min Lim1, Jun-Seok Lee6, Hoon Ryu1,7, Ae Nim Pae1 and Yun Kyung Kim1,2
1Center for Brain Disorders, Brain Science Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea.
2Division of Bio-Medical Science & Technology, KIST School, Korea University of Science and Technology (UST), Seoul 02792, Republic of Korea.
3Advanced Analysis Center, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea.
4Department of Life Sciences, Korea University, Seoul 02841, Korea.
5Boston University Alzheimer’s disease Research Center and VA Boston Health care System, Boston, MA 02130, USA.
6Department of Pharmacology, Korea University College of Medicine, Seoul 02792, Republic of Korea.
7Boston University Alzheimer’s disease Research Center and Department of Neurology, Boston University School of Medicine, Boston, MA 02118, USA.
8These authors contributed equally: Sungsu Lim, Seulgi Shin.
Corresponding authors : Correspondence to Ae Nim Pae or Yun Kyung Kim.
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. 14C-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 TauP301L-BiFC mouse model. Our data present the potential of levosimendan as a disease-modifying drug for tauopathies.
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