Structural conversion of neurotoxic amyloid-β(1–42) oligomers to fibrils
By Mahiuddin Ahmed, Judianne Davis, Darryl Aucoin, Takeshi Sato, S. Ahuja, S. Aimoto, J. Elliott, W. V. Van Nostrand, Steven O. Smith. Nature Structural &Molecular Biology, 2010
943 citations recorded by the source corpus.
The amyloid-β1–42 (Aβ42) peptide rapidly aggregates to form oligomers, protofibils and fibrils en route to the deposition of amyloid plaques associated with Alzheimer's disease. We show that low-temperature and low-salt conditions can stabilize disc-shaped oligomers (pentamers) that are substantially more toxic to mouse cortical neurons than protofibrils and fibrils. We find that these neurotoxic oligomers do not have the β-sheet structure characteristic of fibrils. Rather, the oligomers are composed of loosely aggregated strands whose C termini are protected from solvent exchange and which have a turn conformation, placing Phe19 in contact with Leu34. On the basis of NMR spectroscopy, we show that the structural conversion of Aβ42 oligomers to fibrils involves the association of these loosely aggregated strands into β-sheets whose individual β-strands polymerize in a parallel, in-register orientation and are staggered at an intermonomer contact between Gln15 and Gly37.
Subfields: Biomaterials, Geometry and Topology, Physiology
View Paper: https://www.semanticscholar.org/paper/6197dbebf67f28c84671751e623886c15d4344cd
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Citations in the corpus
- Protein Misfolding, Amyloid Formation, and Human Disease: A Summary of Progress Over the Last Decade. (2017, background): “This analysis indicates that monomers, dimers, and trimers (4–14 kDa) show minimal toxicity (174, 177, 183); that the maximum toxicity in terms of monomer equivalents is exhibited by small oligomers, such as PFOs (18–90 kDa) (173, 174) and ADDLs (36–72 kDa) (204, 205); and that toxicity then decreas”
- Atomic-resolution structure of a disease-relevant Aβ(1–42) amyloid fibril (2016, background): “(2015) Peptide dimer structure in an Aβ(1-42) fibril visualized with cryo-EM.”