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

The self-association of the amyloid beta (A beta) peptide into toxic oligomers is implicated in the early events leading to Alzheimer's disease (AD). Blocking the formation of A beta 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 A beta 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 A beta inhibitors from our work to demonstrate the applications of such experiments, i.e. EGCG and human serum albumin.