Liquid-liquid phase-separated tau colocalizes with and stabilizes Aβ oligomers

Abstract

Protein aggregation is a hallmark of neurodegenerative diseases, where misfolded proteins accumulate into insoluble deposits. Emerging studies indicate that liquid-liquid phase separation (LLPS) may serve as a transient stage in the transition from monomers to amyloid fibrils for several proteins implicated in neurological disorders. In this study, we investigated the interplay between tau and off-pathway oligomers of amyloid-beta (Aβ), the two key proteins in Alzheimer’s disease (AD). Our findings demonstrate that tau condensates act as reservoirs for Aβ oligomers under LLPS conditions. Inside the tau condensates, Aβ oligomers reduced tau dynamics and formed discrete puncta, indicating a conducive environment for Aβ oligomer clustering. In contrast, in the absence of LLPS conditions, tau and Aβ oligomers formed solid-like co-aggregates with distinct morphologies. Tau significantly affected the kinetics of Aβ assembly, stabilizing off-pathway oligomers and inhibiting their replacement by amyloid fibrils. Our results highlight interactions between higher-order assemblies of tau and Aβ that may contribute to AD pathology. Protein aggregation is a hallmark of neurodegenerative diseases but locating the primary pathological species among the many reported forms of tau and amyloid-beta (Aβ) proteins, the two key proteins in Alzheimer’s disease, remains challenging. Here, the authors study the interplay between tau and off-pathway oligomers of Aβ, showing that tau condensates act as reservoirs for Aβ oligomers under liquid-liquid phase separation conditions, with Aβ oligomers reducing tau dynamics, potentially providing a conducive environment for Aβ oligomer clustering.