Neurofibrillary tangles consisting of aggregated tau protein is one pathological characteristic of Alzheimer’s disease. How this aberrant behavior of tau, normally a microtubule-stabilizing protein, is initiated in the misfolding process is not yet fully understood. Droplet/condensate formation via liquid-liquid phase separation (LLPS) has emerged as an important step. In this study, we identify the chaperone activity of the BRICHOS protein domain toward tau protein. A combination of biophysical methods in vitro, among them, nuclear magnetic resonance (NMR), microscopy, and fluorescence spectroscopy, as well as ex vivo electrophysiology toxicity measurements were applied. We found that native tau aggregation is inhibited by BRICHOS in a concentration-dependent manner, as monitored by fluorescence aggregation kinetics (C. Mörman. et al. 2025. J Am Chem Soc .147(27), 23504–23518). To test if the inhibitory effect originates from monomeric interactions, solution NMR measurements were performed, which elucidated a weak micromolar interaction. Tau protein forms droplets readily in vitro. Interestingly, BRICHOS regulates the LLPS behavior of tau in the determined phase diagrams, and inhibited LLPS-facilitated amyloid fibril formation. We also investigated the BRICHOS binding toward tau droplets, revealing a similar but stronger binding. BRICHOS is incorporated into Tau droplets and alternates the dynamic tau behavior. At high concentrations, droplet formation is completely prevented. Further, BRICHOS suppresses tau-associated neurotoxicity. The results were rationalized in a model where BRICHOS regulates tau droplet formation and subsequent aggregation via monomeric interactions and specific inhibition of secondary nucleation. This study can facilitate how modulated droplet formation and amyloid fibril binding are linked to the inhibitory effect of protein aggregation mediated by molecular chaperones. The outlook covers posttranslational modifications of tau such as phosphorylation and disease-related mutants, including the BRICHOS impact, to expand our current understanding of tau LLPS in pathology.
Mörman et al. (Sun,) studied this question.