Imaging Aβ aggregation by liquid-phase transmission electron microscopy

The amyloid beta peptide (Aβ) readily aggregates into amyloid fibrils. This process has been the subject of intense investigations since it is associated with Alzheimer’s disease. However, it has been highly challenging to observe the microscopic steps in the aggregation reaction directly and to characterize the oligomeric assemblies formed as intermediates. To achieve this goal, we apply liquid-phase transmission electron microscopy (LTEM) in combination with all-atom molecular dynamics simulations. Our results offer an initial visualization of the dynamics of Aβ oligomers, the formation of Aβ protofibrils, and the presence of Aβ oligomers on the surface of Aβ fibrils. This work illustrates how the application of LTEM to the study of protein aggregation in solution enables the imaging of key molecular events in the aggregation process of Aβ.