Methylene blue accelerates liquid-to-gel transition of tau condensates impacting tau function and pathology

Abstract

Preventing tau aggregation is a potential therapeutic strategy in Alzheimer’s disease and other tauopathies. Recently, liquid–liquid phase separation has been found to facilitate the formation of pathogenic tau conformations and fibrillar aggregates, although many aspects of the conformational transitions of tau during the phase transition process remain unknown. Here, we demonstrate that the tau aggregation inhibitor methylene blue promotes tau liquid–liquid phase separation and accelerates the liquid-to-gel transition of tau droplets independent of the redox activity of methylene blue. We further show that methylene blue inhibits the conversion of tau droplets into fibrils and reduces the cytotoxicity of tau aggregates. Although gelation slows down the mobility of tau and tubulin, it does not impair microtubule assembly within tau droplets. These findings suggest that methylene blue inhibits tau amyloid fibrillization and accelerates tau droplet gelation via distinct mechanisms, thus providing insights into the activity of tau aggregation inhibitors in the context of phase transition.

Rational Design of Phytovirucide that Inhibits the Nucleocapsid Condensates of Tomato Spotted Wilt Virus

“…We discovered that the introduction of basic amine groups is critical, enabling classi cation as as pHresponsive drugs (CADs). Our observations show that most biomolecular condensate inhibitors identi ed through high-content screening methods in the medical eld possess alkalic groups 20,[42][43][44][45][46] .…”

“…We have noticed that the phase separation modulators through highthroughput screening method appear to possess properties of CADs (Fig. 1b) [42][43][44][45][46] . Noteworthy, an increasing number of studies emphasize the crucial role of pH in the formation of condensates [47][48][49][50] .…”

An NMR-guided approach for identifying co-factors in boosting the Pfu DNA polymerase

“…Chaperones essentially serve as guides for client proteins, reducing the likelihood of denaturation, thereby, prolonging the lifetime and activity of client proteins. Additionally, plenty of studies also suggest that small, low-molecular-weight compounds can be effective in inhibiting protein aggregation or enabling proteins to restore their functions (15,16). These small molecules are referred to as chemical chaperones, and they are believed to non-specifically stabilize proteins, facilitating their proper folding.…”