title: Amyloid-β forms fibrils by nucleated conformational conversion of oligomers.
abstract: Amyloid-β amyloidogenesis is reported to occur via a nucleated polymerization mechanism. If this is true, the energetically unfavorable oligomeric nucleus should be very hard to detect. However, many laboratories have detected early nonfibrillar amyloid-β oligomers without observing amyloid fibrils, suggesting that a mechanistic revision may be needed. Here we introduce Cys-Cys-amyloid-β(1-40), which cannot bind to the latent fluorophore FlAsH as a monomer, but can bind FlAsH as an nonfibrillar oligomer or as a fibril, rendering the conjugates fluorescent. Through FlAsH monitoring of Cys-Cys-amyloid-β(1-40) aggregation, we found that amyloid-β(1-40) rapidly and efficiently forms spherical oligomers in vitro (85% yield) that are kinetically competent to slowly convert to amyloid fibrils by a nucleated conformational conversion mechanism. This methodology was used to show that plasmalogen ethanolamine vesicles eliminate the proteotoxicity-associated oligomerization phase of amyloid-β amyloidogenesis while allowing fibril formation, rationalizing how low concentrations of plasmalogen ethanolamine in the brain are epidemiologically linked to Alzheimer's disease.
authors.affiliation: Department of Chemistry, The Scripps Research Institute and The Skaggs Institute for Chemical Biology, La Jolla, California, USA.
authors.forename: Jiyong
authors.initials: J
authors.lastname: Lee
authors.forename: Elizabeth K
authors.initials: EK
authors.lastname: Culyba
authors.forename: Evan T
authors.initials: ET
authors.lastname: Powers
authors.forename: Jeffery W
authors.initials: JW
authors.lastname: Kelly
mesh_terms: D000682:Amyloid / Q000737:chemistry*; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D004151:Dipeptides / Q000737:chemistry; D019856:Ethanolamine / Q000737:chemistry; D006801:Humans; D010446:Peptide Fragments / Q000737:chemistry*; D010955:Plasmalogens / Q000737:chemistry; D058105:Polymerization; D011485:Protein Binding; D011487:Protein Conformation
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D004151:Dipeptides; D010446:Peptide Fragments; D010955:Plasmalogens; C078592:amyloid beta-protein (1-40); C046557:cysteinylcysteine; D019856:Ethanolamine