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KMID : 0620920230550030612
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Experimental & Molecular Medicine
2023 Volume.55 No. 3 p.612 ~ p.627
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Levosimendan inhibits disulfide tau oligomerization and ameliorates tau pathology in TauP301L-BiFC mice
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Lim Sung-Su
Yang Su-Jin
Sung Yoon-Sik
Lee Ha-Eun
Kim Kyu-Hyeon
Shin Yun-Mi
Lee Gwan-Ho
Hira Aziz
Nataliia Lukianenko
Kang Dong-Min
Nicolette Boesen
Jeong Hyean-Jeong
Aizhan Abdildinova
Lee Jung-Hee
Yu Byung-Yong
Lim Sang-Min
Lee Jun-Seok
Ryu Hoon
Pae Ae-Nim
Kim Yun-Kyung
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Abstract
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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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KEYWORD
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Alzheimer′s disease, Drug development
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