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

The onset and development of Alzheimer’s disease (AD) is linked to the accumulation of pathological aggregates formed from the normally monomeric amyloid-β peptide within the central nervous system. These Aβ aggregates are increasingly successfully targeted with clinical therapies, but 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. Our results reveal that 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 are prone to undergo a liquid-to-solid transition leading to the formation amyloid fibrils. These findings uncover the liquid-liquid phase separation behaviour of the Aβ peptide, and reveal a new molecular step very early in the amyloid-β aggregation cascade that can form the basis for novel therapeutic intervention strategies. Significance statement The hallmark of Alzheimer’s disease is the abnormal buildup of the normally soluble amyloid β protein aggregates in the central nervous system. While the molecular mechanisms at the late stages of the amyloid β aggregation cascade are well understood, the initial steps remained elusive until now. Our current study demonstrates that amyloid β undergoes liquid-liquid phase separation on lipid surfaces, which triggers primary nucleation and initiates the amyloid β aggregation cascade. This newly identified step in the molecular mechanism of Alzheimer’s disease represents a promising target for the development of alternative innovative therapeutic strategies. ### Competing Interest Statement The authors have declared no competing interest. * AD : Alzheimer’s disease ALS : Amyotrophic lateral sclerosis APP : Amyloid precursor protein DMPC : 1,2-Dimyristoyl-sn-glycero-3-phosphocholine FRAP : Fluorescence recovery after photobleaching FUS : Fused in Sarcoma LLPS : Liquid-liquid phase separation PD : Parkinson’s disease PDMS : Polydimethylsiloxane TIRF : Total internal reflection fluorescence