Nanoscale Dynamics of Amyloid β-42 Oligomers As Revealed by High-Speed Atomic Force Microscopy

Amyloid beta-protein (A beta) oligomers are emerging as potent neurotoxic species in Alzheimer's disease pathogenesis. Detailed characterization of oligomer structure and dynamics is necessary to develop oligomer-specific therapeutic agents. However, oligomers exist transiently, which complicates their structural analysis. One approach to mitigate these problems has been photochemical cross linking of native oligomers. In these states, the oligomers can be isolated and purified for physical and chemical studies. Here we characterized the structure of isolated cross-linked A beta 42 trimers, pentamers, and heptamers with atomic force microscopy (AFM) imaging and probed their dynamics in solution using time-lapse high-speed AFM. This technique enables visualization of the structural dynamics of the oligomers at nanometer resolution on a millisecond time scale. Results demonstrate that cross-linked pentamers and heptamers are very dynamic fluctuating between a compact single-globular and multiglobular assemblies. Trimers remain in their single-globular geometry that elongates adopting an ellipsoidal shape. Biological significance of oligomers dynamics is discussed.