Amyloid-β forms fibrils by nucleated conformational conversion of oligomers
Open Access
- 31 July 2011
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Chemical Biology
- Vol. 7 (9), 602-609
- https://doi.org/10.1038/nchembio.624
Abstract
FlAsH fluorescence and thioflavin-to-FlAsH FRET are used to distinguish amyloid-β oligomer formation from fibril formation, supporting rapid oligomer formation prior to fibril formation—consistent with a nucleated conformational conversion mechanism—that can be modulated by certain Alzheimer's disease–linked mutations or lipids. 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-β1–40, 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-β1–40 aggregation, we found that amyloid-β1–40 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.Keywords
This publication has 52 references indexed in Scilit:
- The Japanese Mutant Aβ (ΔE22-Aβ1−39) Forms Fibrils Instantaneously, with Low-Thioflavin T Fluorescence: Seeding of Wild-Type Aβ1−40 into Atypical Fibrils by ΔE22-Aβ1−39Biochemistry, 2011
- Structural conversion of neurotoxic amyloid-β1–42 oligomers to fibrilsNature Structural & Molecular Biology, 2010
- Bipartite Tetracysteine Display Requires Site Flexibility for ReAsH CoordinationChemBioChem, 2009
- Conformational detection of p53’s oligomeric state by FlAsH FluorescenceBiochemical and Biophysical Research Communications, 2009
- Amyloid-β protein oligomerization and the importance of tetramers and dodecamers in the aetiology of Alzheimer's diseaseNature Chemistry, 2009
- Polyglutamine disruption of the huntingtin exon 1 N terminus triggers a complex aggregation mechanismNature Structural & Molecular Biology, 2009
- Cross-Strand Split Tetra-Cys Motifs as Structure Sensors in a β-Sheet ProteinCell Chemical Biology, 2008
- Amyloid-β protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memoryNature Medicine, 2008
- Surveying polypeptide and protein domain conformation and association with FlAsH and ReAsHNature Chemical Biology, 2007
- Polyglutamine protein aggregates are dynamicNature, 2002