The Alzheimer’s Aβ peptide forms biomolecular condensates that trigger amyloid aggregation

Abstract

AbstractThe onset and development of Alzheimer’s disease (AD) involves the accumulation of pathological aggregates formed from the normally monomeric amyloid-β peptide within the central nervous system. While clinical therapies successfully target these aggregates, the fundamental molecular steps that trigger the initial nucleation event leading to the conversion of monomeric Aβ peptide into pathological aggregates remain unknown. Here we show that the Aβ peptide can form biomolecular condensates on lipid bilayers both in molecular assays and in living cells. These Aβ condensates can significantly accelerate the primary nucleation step in the amyloid conversion cascade that leads to the formation of amyloid aggregates and plaque. We show that Aβ condensates contain phospholipids, are intrinsically heterogenous, and undergo a liquid-to-solid transition leading to the formation of amyloid fibrils. Unveiling the liquid-liquid phase separation of Aβ peptide identifies a novel, early molecular step in the AD aggregation cascade, offering potential for innovative therapeutic interventions.