3D nanoscale imaging of amyloid-β oligomer interactions with extracellular vesicles by cryo-ET

• 成果类型: Article
• 署名作者: Khursheed, Anum; Shang, Qi; Zhang, Hui; Tian, Yao; Szwedziak, Piotr; Volkov, Vladimir A.; Viles, John H.
• 署名单位: University of London; Queen Mary University London; South Central Minzu University; University of Zurich
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2610068123
• 发表日期: 2026-07-21
• 页码: e2610068123
• 关键词: Alzheimer's; annular; protofibril; membrane; cryo-em; alzheimers-disease; protein; exosomes; receptor; accumulation; pathogenesis; hypothesis; peptides; channels; neurons

摘要

Central to Alzheimer's disease pathology are prefibrillar oligomer assemblies of amyloid-beta (A beta) peptide. A widely discussed hypothesis proposes that amyloid-beta oligomers insert into neuronal lipid membranes, disrupting their integrity and causing a loss of cellular homeostasis in Alzheimer's disease. This membrane disruption is believed to be a major source of A beta-induced neurotoxicity. Cryo electron tomography (cryo-ET) has facilitated 3D nanoscale imaging of A beta-membrane interactions under near-native conditions. Analyses of small extracellular vesicles (sEVs) reveals that A beta oligomers including annular and curvilinear extended oligomers (CLEOs) exhibit extensive binding to cell-derived lipid membranes, including insertion into and carpeting of the lipid bilayer. Notably, these oligomeric assemblies were also internalized and concentrated within the cell-derived exosomes and other small sEVs. Enrichment of A beta oligomers within the vesicles typically ranged between 5 to 20 times the external A beta levels depending on the vesicle size and curvature. In contrast, monomeric and fibrillar forms of A beta displayed minimal membrane interaction. Once internalized CLEOs appear to be trapped in an oligomeric form and do not readily go on to form fibrils. Studies with vesicles of brain lipid extract indicate the A beta internalization does not require the presence of a membrane protein. Our in vitro studies underscore the membrane-disruptive capacity of oligomeric A beta species and suggest a role of sEVs in concentrating toxic A beta oligomers and transporting oligomers across the brain interstitium.