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.

Automated summary

The self-assembly process of amyloid-beta peptides in Alzheimer's disease was studied using time-resolved solid-state NMR and light scattering experiments. Results showed that within one millisecond, beta-strand conformations and intermolecular contacts between different segments of amyloid-beta molecules started to form. These findings suggest that the initial structures of oligomers are different from those of protofibrils and fibrils.