Time-resolved solid-state nuclear magnetic resonance studies of amyloid-β oligomer formation

Although much is known about the molecular structures of mature amyloid fibrils, based primarily on extensive studies by solid-state nuclear magnetic resonance (ssNMR) and cryogenic electron microscopy (cryo-EM), relatively little is known about the structures of oligomers that form in the initial stages of self-assembly by amyloid-forming peptides and proteins. Time-resolved ssNMR methods with millisecond time resolution have been developed recently to address problems of this type, based on a combination of technologies for rapid mixing, rapid freezing, and low-temperature ssNMR with signal enhancements from dynamic nuclear polarization (DNP). This chapter reviews current time-resolved ssNMR methods, discusses aspects of these methods that have not been emphasized in previous publications, and summarizes information about the molecular mechanism of amyloid-β oligomer formation obtained from time-resolved ssNMR.