Lipid- induced condensate formation from the Alzheimer's Aβ peptide triggers amyloid aggregation

• 成果类型: Article
• 署名作者: Sneideriene, Greta; Diaz, Alicia Gonzalez; Adhikari, Sourav Das; Wei, Jiapeng; Michaels, Thomas; Sneideris, Tomas; Linse, Sara; Vendruscolo, Michele; Garai, Kanchan; Knowles, Tuomas P. J.
• 署名单位: University of Cambridge; Tata Institute of Fundamental Research (TIFR); Swiss Federal Institutes of Technology Domain; ETH Zurich; Swiss Federal Institutes of Technology Domain; ETH Zurich; Lund University; University of Cambridge
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-12965
• DOI: 10.1073/pnas.2401307122
• 发表日期: 2025-01-28
• 关键词: liquid phase-separation; protein aggregation; membrane; oligomers; association; metabolism; diffusion; monomer; occurs

摘要

The onset and development of Alzheimer's disease is linked to the accumulation of pathological aggregates formed from the normally monomeric amyloid-beta peptide within the central nervous system. These A beta aggregates are increasingly successfully targeted with clinical therapies at later stages of the disease, but the fundamental molecular steps in early stage disease that trigger the initial nucleation event leading to the conversion of monomeric A beta peptide into pathological aggregates remain unknown. Here, we show that the A beta peptide can form biomolecular condensates on lipid bilayers both in molecular assays and in living cells. Our results reveal that these A beta condensates can significantly accelerate the primary nucleation step in the amyloid conversion cascade that leads to the formation of amyloid aggregates. We show that A beta condensates contain phospholipids, are intrinsically heterogeneous, and are prone to undergo a liquid- to- solid transition leading to the formation of amyloid fibrils. These findings uncover the liquid-liquid phase separation behavior of the A beta peptide and reveal a molecular step very early in the amyloid-beta aggregation process.