Early events in amyloid-β self-assembly probed by time-resolved solid state NMR and light scattering

Self-assembly of amyloid-beta peptides leads to oligomers, protofibrils, and fibrils that are likely instigators of neurodegeneration in Alzheimer's disease. We report results of time-resolved solid state nuclear magnetic resonance (ssNMR) and light scattering experiments on 40-residue amyloid-beta (A beta 40) that provide structural information for oligomers that form on time scales from 0.7 ms to 1.0 h after initiation of self-assembly by a rapid pH drop. Low-temperature ssNMR spectra of freeze-trapped intermediates indicate that beta-strand conformations within and contacts between the two main hydrophobic segments of A beta 40 develop within 1 ms, while light scattering data imply a primarily monomeric state up to 5 ms. Intermolecular contacts involving residues 18 and 33 develop within 0.5 s, at which time A beta 40 is approximately octameric. These contacts argue against beta-sheet organizations resembling those found previously in protofibrils and fibrils. Only minor changes in the A beta 40 conformational distribution are detected as larger assemblies develop. Here the authors report time-resolved experiments showing that amyloid-beta peptide molecules become partially structured even before they adhere to one another, within one millisecond. Peptide conformations change only slightly as assemblies grow in size for many minutes.