New Study Shows How Two Alzheimer's Proteins Trigger Brain Damage Together
Researchers have discovered how amyloid-beta, one of Alzheimer's hallmark proteins, acts as a chemical catalyst to accelerate the toxic aggregation of tau protein in the brain. The finding could reshape drug development strategies, suggesting companies should target the interaction between the two proteins rather than attacking them separately.
Originaltitel: 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.