Levosimendan inhibits disulfide tau oligomerization and ameliorates tau pathology in TauP301L-BiFC mice

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 Tau^P301L-BiFC mouse model. Our data present the potential of levosimendan as a disease-modifying drug for tauopathies.

Alzheimer’s disease: A tool for preventing toxic tangles

The discovery that an already approved drug can disrupt tau protein aggregation in cultured cells and live mice could guide the development of new therapies for Alzheimer’s. Tau plays an important role in organizing the internal structure of neurons, but in neurodegenerative disease is seen to form abnormal assemblies that are toxic to cells. Researchers led by Ae Nim Pae and Yun Kyung Kim at the Korea Institute of Science and Technology, Seoul, South Korea have devised an assay that allowed them to identify agents that actively interfere with this process. Levosimendan, a drug approved for heart failure, broke up tau aggregates in cell culture and reduced cognitive symptoms in a mouse model of tau-induced neurodegeneration. Further investigation of levosimendan’s mode of action could yield interventions that slow or prevent Alzheimer’s progression.