Molecular plasticity regulates oligomerization and cytotoxicity of the multipeptide-length amyloid-β peptide pool

Current therapeutic approaches under development for Alzheimer disease, including gamma-secretase modulating therapy, aim at increasing the production of A beta(1-38) and A beta(1-40) at the cost of longer A beta peptides. Here, we consider the aggregation of A beta(1-38) and A beta(1-43) in addition to A beta(1-40) and A beta(1-42), in particular their behavior in mixtures representing the complex in vivo A beta pool. We demonstrate that A beta(1-38) and A beta(1-43) aggregate similar to A beta(1-40) and A beta(1-42), respectively, but display a variation in the kinetics of assembly and toxicity due to differences in short timescale conformational plasticity. In biologically relevant mixtures of A beta, A beta(1-38) and A beta(1-43) significantly affect the behaviors of A beta(1-40) and A beta(1-42). The short timescale conformational flexibility of A beta(1-38) is suggested to be responsible for enhancing toxicity of A beta(1-40) while exerting a cyto-protective effect on A beta(1-42). Our results indicate that the complex in vivo A beta peptide array and variations thereof is critical in Alzheimer disease, which can influence the selection of current and new therapeutic strategies.