Visualizing and trapping transient oligomers in amyloid assembly pathways

Oligomers which form during amyloid fibril assembly are considered to be key contributors towards amyloid disease. However, understanding how such intermediates form, their structure, and mechanisms of toxicity presents significant challenges due to their transient and heterogeneous nature. Here, we discuss two different strategies for addressing these challenges: use of (1) methods capable of detecting lowly-populated species within complex mixtures, such as NMR, single particle methods (including fluorescence and force spectroscopy), and mass spectrometry; and (2) chemical and biological tools to bias the amyloid energy landscape towards specific oligomeric states. While the former methods are well suited to following the kinetics of amyloid assembly and obtaining low-resolution structural information, the latter are capable of producing oligomer samples for high-resolution structural studies and inferring structure-toxicity relationships. Together, these different approaches should enable a clearer picture to be gained of the nature and role of oligomeric intermediates in amyloid formation and disease.

Automated summary

Understanding the formation and toxicity mechanisms of oligomers during amyloid fibril assembly is crucial for amyloid diseases. By utilizing methods such as NMR, mass spectrometry, and tools to manipulate the amyloid energy landscape, researchers can gain insights into the nature and role of these oligomeric intermediates. These approaches allow for the study of kinetics, structural information, and structure-toxicity relationships of oligomers, providing a clearer picture of their contribution to amyloid formation and disease.