Aggregated amyloid-β (Aβ) peptide is implicated in the pathology of Alzheimer's disease. In vitro and in vivo, these aggregates are found in a variety of morphologies, including globular oligomers and linear fibrils, which possess distinct biological activities. However, known chemical probes, including the dyes thioflavin T and Congo Red, appear to lack selectivity for specific amyloid structures. To identify molecules that might differentiate between these architectures, we employed a fluorescence-based interaction assay to screen a collection of 68 known Aβ ligands against preformed oligomers and fibrils. In these studies, we found that the fluorescence of five indole-based compounds was selectively quenched (~15%) in the presence of oligomers, but remained unchanged after addition of fibrils. These results suggest that indoles might be complementary to existing chemical probes for studying amyloid formation in vitro.

Aggregated amyloid‐β (Aβ) peptide is implicated in the pathology of Alzheimer's disease (AD). In vitro and in vivo, these aggregates are found in a variety of configurations, including globular oligomers and linear fibrils. Despite being composed of identical monomer units, these different quaternary configurations give rise to distinct biological effects; for example, recent evidence suggests that oligomers might play a key role in AD pathology. To identify unique molecular features that might differentiate these architectures, we employed a fluorescence‐based interaction assay to screen a collection of 68 known Aβ ligands. Using this approach, we found that most of the small molecules, including the well‐known compounds Bis‐ANS and Congo Red, interact equally well with both Aβ oligomers and fibrils. However, the fluorescence of five indole‐based compounds was selectively quenched in the presence of oligomers, but remained unchanged after addition of fibrils. These results suggest that amino acids capable of quenching indole fluorescence, such as Lys16, Phe19, Phe20, or Lys28, are relatively exposed in oligomers and buried in fibrils. These differences in accessibility may encompass one mechanism by which different amyloid structures give rise to distinct biological outcomes.