Alzheimer’s Aβ catalyzes Tau phase separation and aggregation via early nanocluster solubilization

Extracellular amyloid-beta (Aβ) plaques and intracellular neurofibrillary tangles (NFTs) composed of hyperphosphorylated Tau are the two main pathological hallmarks of Alzheimer's disease (AD). Although the co-occurrence and synergistic effects of Aβ and Tau are well established, the mechanisms underlying their interplay in a biomolecular condensate environment remain unclear. Here we show that Aβ40 does not undergo liquid-liquid phase separation (LLPS) but significantly enhances Tau phase separation and is recruited into Tau condensates. This recruitment alters condensate physicochemical properties, accelerates liquid-to-solid maturation, promotes Tau amyloid fibril formation, and increases Tau-mediated cytotoxicity. Notably, prior to condensate formation, Aβ40 transiently solubilizes Tau nanoclusters into smaller species. Simulations further indicate that early interactions are non-specific and mediated by Tau repeat domains, ultimately promoting pathogenic aggregation. These findings support a model wherein Aβ act as a catalyst for Tau condensation and fibrillation towards pathological aggregates by solubilizing Tau nanoclusters during early phase interactions.