Intraneuronal deposits of tau fibrils (PHFs and NFTs) are the pathological hallmark in a group of neurodegenerative diseases called tauopathies. Chemically and structurally modified tau aggregates and accumulates in neurons. The dissociated tau becomes a substrate that is susceptible to cytosolic enzymes, which modify the states of tau phosphorylation, acetylation, or proteolytic cleavage 6, 7. Under pathological conditions, the charge balance between tau and microtubules is disrupted, and tau dissociates from the microtubules 5. Upon binding, tau stabilizes microtubules and promotes microtubule assembly, which is critical for axonal outgrowth 3, 4. The lysine residues play a role in binding negatively charged microtubules 2. Tau is naturally an extremely soluble protein and contains many positively charged lysine residues 1. Our data present the potential of levosimendan as a disease-modifying drug for tauopathies. Levosimendan displayed robust potency against tau oligomerization and rescued cognitive declines induced by tauopathy in the Tau P301L-BiFC mouse model. 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. In addition, levosimendan disassembles tau oligomers into monomers, rescuing neurons from aggregation states. 14C-isotope labeling of levosimendan revealed that levosimendan covalently bound to tau cysteines, directly inhibiting disulfide-linked 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. Working toward tau-targeted drug discovery, our group has developed a tau-BiFC platform to monitor and quantify tau oligomerization. However, progress has been slow because detecting tau oligomers in the cellular context is difficult. Accordingly, preventing tau oligomerization has become an important therapeutic strategy to treat tauopathies, including Alzheimer’s disease.

Tau oligomers play critical roles in tau pathology and are responsible for neuronal cell death and transmitting the disease in the brain.

Graphpad prism 6