Liquid-solid coexistence at single fibril resolution during tau condensate ageing

Aggregated fibrillar tangles of the microtubule-associated protein tau are a hallmark of Alzheimer’s disease. It is becoming increasingly clear that a key process that can trigger the formation of such tau tangles is the aberrant ageing of biomolecular condensates of tau formed via liquid-liquid phase separation. This ageing process affects the overall mechanical and structural properties of the condensates, but the molecular-level mechanisms by which aggregation takes place in the condensates have remained elusive. Here, by tracking individual tau molecules inside the condensates by single molecule microscopy we show that the ageing process is characterized by the co-existence of a growing solid phase of tau within a dense liquid phase. The liquid phase is increasingly confined to the pores of the growing fibril gel network, but maintains its initial viscosity. These findings add a spatial dimension to the ageing of condensates and demonstrate that spatial heterogeneity is a key feature of the liquid-to-solid transition of tau.