A solution NMR toolset to probe the molecular mechanisms of amyloid inhibitors

The self-association of the amyloid beta (Aβ) peptide into toxic oligomers is implicated in the early events leading to Alzheimer's disease (AD). Blocking the formation of Aβ oligomers and their interactions with the extracellular and cellular environment through small molecules and biopharmaceuticals is therefore a promising preventive strategy for AD. However, given the heterogeneity and transient nature of the Aβ oligomeric species, detailed structural and kinetic characterizations of such oligomers and oligomer:inhibitor complexes have proven to be challenging. Here, we discuss recent advancements in solution NMR that have been instrumental in overcoming these limitations and we provide two representative examples of Aβ inhibitors from our work to demonstrate the applications of such experiments, i.e. EGCG and human serum albumin.