Structural conversion of neurotoxic amyloid-β1–42 oligomers to fibrils

Abstract

Amyloid-β42 (Aβ42) peptide aggregates to form oligomers, protofibrils and fibrils en route to the deposition of amyloid plaques associated with Alzheimer's disease. Structural and functional analyses show that the conversion of Aβ42 oligomers to fibrils is accompanied by reduced neurotoxicity and involves the formation of parallel, in-register β-sheets that are staggered at an intermolecular contact. 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.