(Invited) Time-Lapse AFM Visualization of Aggregation of Amyloid Proteins at Physiologically Relevant Concentrations

Abstract

The aggregation of amyloid beta (Aβ) is a self-assembly process that results in the production of fibrillar structures along with neurotoxic aggregates. However, in the vast majority studies in vitro the required Aβ concentrations is several orders higher of the physiological relevant concentrations of Aβ; no aggregation is observed at physiological low nanomolar range of Aβ. This suggests that the assembly of Aβ in aggregates in vivo utilizes pathways different from those used in experiments in vitro. We have discovered recently that surface plays a role of catalyst allowing the self-assembly of amyloid aggregates to occur at physiologically relevant concentrations. We proposed a model in which the monomers transiently immobilized on the surfaces work as nuclei for the next aggregation step. The model was verified by experimental time-dependent AFM measurements. AFM studies of aggregation of Aβ on supported phospholipid bilayer revealed a strong effect of the membrane composition on the surface aggregation catalysis. We combined AFM experimental studies with all-atom molecular dynamic (MD) simulations to characterize the on-surface self-assembly process of amyloid proteins. MD simulations show that the surface-protein interactions induce a conformational transition of the monomer facilitating binding of another molecule. Importantly, even transient interactions of amyloid beta protein with the membrane bilayer facilitate sampling of the energy profile allowing for the monomer to adopt the β rich conformations responsible for the assembly of conformationally stable oligomers. A membrane-mediated aggregation catalysis explains a number of observations associated with the development of Alzheimer's disease. The affinity of Aβmonomers to the membrane surface is the major factor defining the aggregation process rather than Aβ concentration. Therefore, the development of potential preventions for the interaction of monomeric amyloids with membrane can help control the aggregation process.