Targeting soluble misfolded oligomers in anti-amyloid research

Protein misfolding drives a range of non-curable diseases, such as Alzheimer disease, Parkinson disease, type 2 diabetes and Huntington disease, that devastate tens of millions of patients each year. The pathological proteins are misfolded into soluble oligomers, which eventually evolve into insoluble amyloid plaques. Increasing evidence suggests that soluble oligomers are the primary cytotoxic species leading to amyloidoses. However, the transient, heterogeneous and low-abundance nature of soluble oligomers makes it extremely challenging to study these species using conventional methods. This Review surveys emerging chemical tools developed for in vitro detection, separation and analysis of soluble amyloid oligomers. We exemplify how the present arsenal can be extended to construct individual amyloid oligomers as potential drug targets. Finally, we summarize their technical limits and discuss possibilities of adapting these chemical tools to target specific soluble oligomers in the fight against amyloidoses.