A long-lived aβ oligomer resistant to fibrillization.

The hydrophobic A beta peptide is highly aggregation prone; it first forms soluble oligomers, which then convert into the amyloid fibrils found in the cerebral plaques of Alzheimer's disease. It is generally understood that as the peptide concentration of A beta increases, the fibrillization process is accelerated, but we examine the limits on this phenomenon. We found that once a threshold concentration of A beta is exceeded, a stable oligomer is formed at the expense of fibril formation. The suppression of fibril formation was observed by amyloid-binding dye Thioflavin T and solution nuclear magnetic resonance (NMR). Small-angle X-ray scattering, size exclusion chromatography, and analytical ultracentrifugation demonstrated that A beta peptides form a range of compact species, with a dimer being an early highly populated oligomer. Solution NMR allowed us to define the secondary structure of this A beta dimer, which shows interlocking contacts between C-terminal peptide strands. Thus, we present a novel A beta oligomer that resists conversion to fibrils and remains stable for more than one year.