Lim, Sung su Shin, Seul gi Sung, Yoonsik Lee, Haeun Kim, Kyu Hyeon 송지연 Lee, Gwan Ho Aziz, Hira 나탈리아 루키안에넨코 Kang Dong Min 니콜렛 보에센 Hyeanjeong Jeong ABDILDINOVA AIZHAN Junghee Lee Yu, Byung Yong LIM, SANG MIN Jun-Seok Lee Ryu, Hoon Pae, Ae Nim Kim, Yun Kyung 2024-01-12T02:31:29Z 2024-01-12T02:31:29Z 2023-03-22 2023-03 1226-3613 https://pubs.kist.re.kr/handle/201004/75771 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. English 생화학분자생물학회 Levosimendan inhibits disulfide tau oligomerization and ameliorates tau pathology in TauP301L-BiFC mice Article 10.1038/s12276-023-00959-5 1 Experimental & Molecular Medicine, v.55, pp.612 - 627 Experimental & Molecular Medicine 55 612 627 Y scie scopus kci ART002947511 000948740700001 Biochemistry & Molecular Biology Medicine, Research & Experimental Biochemistry & Molecular Biology Research & Experimental Medicine Article; Early Access CARDIAC TROPONIN-C METHYLENE-BLUE ALZHEIMERS-DISEASE ACTIVE METABOLITE IN-VITRO PROTEIN AGGREGATION PHOSPHORYLATION BINDING PHARMACOKINETICS