Kinetics of Amyloid Oligomer Formation.

Abstract

Low-molecular-weight oligomers formed from amyloidogenic peptides and proteins have been identified as key cytotoxins across a range of neurodegenerative disorders, including Alzheimer's disease and Parkinson's disease. Developing therapeutic strategies that target oligomers is therefore emerging as a promising approach for combating protein misfolding diseases. As such, there is a great need to understand the fundamental properties, dynamics, and mechanisms associated with oligomer formation. In this review, we discuss how chemical kinetics provides a powerful tool for studying these systems. We review the chemical kinetics approach to determining the underlying molecular pathways of protein aggregation and discuss its applications to oligomer formation and dynamics. We discuss how this approach can reveal detailed mechanisms of primary and secondary oligomer formation, including the role of interfaces in these processes. We further use this framework to describe the processes of oligomer conversion and dissociation, and highlight the distinction between on-pathway and off-pathway oligomers. Furthermore, we showcase on the basis of experimental data the diversity of pathways leading to oligomer formation in various in vitro and in silico systems. Finally, using the lens of the chemical kinetics framework, we look at the current oligomer inhibitor strategies both in vitro and in vivo.