Solvent exposure of Tyr10 as a probe of structural differences between monomeric and aggregated forms of the amyloid-ß peptide.

Aggregation of amyloid-ß (Aß) peptides is a characteristic pathological feature of Alzheimer's disease. We have exploited the relationship between solvent exposure and intrinsic fluorescence of a single tyrosine residue, Tyr10, in the Aß sequence to probe structural features of the monomeric, oligomeric and fibrillar forms of the 42-residue Aß1-42. By monitoring the quenching of Tyr10 fluorescence upon addition of water-soluble acrylamide, we show that in Aß1-42 oligomers this residue is solvent-exposed to a similar extent to that found in the unfolded monomer. By contrast, Tyr10 is significantly shielded from acrylamide quenching in Aß1-42 fibrils, consistent with its proximity to the fibrillar cross-ß core. Furthermore, circular dichroism measurements reveal that Aß1-42 oligomers have a considerably lower ß-sheet content than the Aß1-42 fibrils, indicative of a less ordered molecular arrangement in the former. Taken together these findings suggest significant differences in the structural assembly of oligomers and fibrils that are consistent with differences in their biological effects.

Single point mutations induce a switch in the molecular mechanism of the aggregation of the Alzheimer's disease associated Aß42 peptide.

Single point mutations in the Alzheimer's disease associated Aß42 peptide are found to alter significantly its neurotoxic properties in vivo and have been associated with early onset forms of this devastating condition. We show that such mutations can induce structural changes in Aß42 fibrils and are associated with a dramatic switch in the fibril-dependent mechanism by which Aß42 aggregates. These observations reveal how subtle perturbations to the physicochemical properties of the Aß peptide, and the structural properties of fibrils that it forms, can have profound effects on the mechanism of its aggregation and pathogenicity.