Abstract
Self-assembly of amyloid-β 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-β (Aβ40) 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 β-strand conformations within and contacts between the two main hydrophobic segments of Aβ40 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 Aβ40 is approximately octameric. These contacts argue against β-sheet organizations resembling those found previously in protofibrils and fibrils. Only minor changes in the Aβ40 conformational distribution are detected as larger assemblies develop.