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.
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We thank M. Ziliox for assistance with the NMR spectroscopy and critical reading of the manuscript. This work was supported by grants from the US National Institutes of Health (RO1-AG027317 to SOS and RO1-NS35781 to W.E.V.N.) and the Cure Alzheimer's Fund to W.E.V.N. NMR measurements were supported by US National Institutes of Health-National Science Foundation instrumentation grants (S10 RR13889 and DBI-9977553) and were carried out in part at the New York Structural Biology Center. Electron microscopy experiments were performed at the Central Microscopy Imaging Center, Stony Brook University.
The authors declare no competing financial interests.
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Ahmed, M., Davis, J., Aucoin, D. et al. Structural conversion of neurotoxic amyloid-β1–42 oligomers to fibrils. Nat Struct Mol Biol 17, 561–567 (2010). https://doi.org/10.1038/nsmb.1799
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