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

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posted on 22.11.2017, 00:00 by Siddhartha Banerjee, Zhiqiang Sun, Eric Y. Hayden, David B. Teplow, Yuri L. Lyubchenko
Amyloid β-protein (Aβ) 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 Aβ42 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.

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