Characterization of chemical exchange between soluble and aggregated states of β-amyloid by solution-state NMR upon variation of salt conditions

Alzheimer's disease (AD) is characterized by the accumulation of insoluble fibrillar aggregates of β-amyloid peptides (Aβ), a 39-42 residue peptide, in the brain of AD patients. It is hypothesized that the disease causing form is not the fibrillar species but an oligomeric Aβ molecule, which is often referred to as the "critical oligomer" of Aβ. We show in this paper that Aβ^1-40 undergoes chemical exchange between a monomeric, soluble state and an oligomeric, aggregated state under physiological conditions. In circular dichroism spectroscopy, we observe for this intermediate an α-helical structure. The oligomer is assigned a molecular weight of >100 kDa by diffusion-ordered spectroscopy - solution-state NMR spectroscopy (NMR). We can show by saturation transfer difference NMR experiments that the oligomer is related to monomeric Aβ. This experiment also allows us to identify the chemical groups that are involved in interactions between mono- and oligomeric Aβ molecules. Variation of the anionic strength in the buffer induces a shift of equilibrium between mono- and oligomeric states and possibly allows for the stabilization of these intermediate structures.