Alzheimerʹs Disease Aβ Peptide Fragment 10–30 Forms a Spectrum of Metastable Oligomers with Marked Preference for N to N and C to C Monomer Termini Proximity

Oligomers of Aβ peptide have been indicated recently as a possible main causative agent of Alzheimerʹs disease. However, information concerning their structural properties is very limited. Here Aβ oligomers are studied by non-covalent complexes mass spectrometry and disulfide rearrangement. As a model molecule, an Aβ fragment spanning residues 10–30 (Aβ10–30) has been used. This model peptide is known to contain the core region responsible for Aβ aggregation to fibrils. Non-covalent complexes mass spectrometry indicates that, at neutral pH, monomers are accompanied by oligomers up to hexamers of gradually decreasing population. H–2H exchange studies and direct monomer exchange rate measurements with the use of 15N labeled peptides and mass spectrometry show a fast exchange of monomeric units between oligomers. Disulfide exchange studies of cysteine tagged Aβ10–30 and its mutant show proximity of N-N and C-C termini of monomers in oligomers. The presented data underscore a dynamic character for pre-nucleation forms of Aβ, however, with a marked tendency for parallel strand orientation in oligomers.