Levosimendan inhibits disulfide tau oligomerization and ameliorates tau pathology in Tau < sup > P301L < /sup > -BiFC mice
Exp Mol Med. 2023 Mar 13. doi: 10.1038/s12276-023-00959-5. Online ahead of print.ABSTRACTTau 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.PMID:36914856 | DOI:10.1038...
Source: Molecular Medicine - Category: Molecular Biology Authors: 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 Source Type: research
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