Molecular Plasticity Regulates Oligomerization and Cytotoxicity of the Multipeptide-length Amyloid-beta Peptide Pool

Contains fulltext : 108708.pdf (Publisher’s version ) (Open Access) Current therapeutic approaches under development for Alzheimer disease, including gamma-secretase modulating therapy, aim at increasing the production of Abeta(1-38) and Abeta(1-40) at the cost of longer Abeta peptides. Here, we consider the aggregation of Abeta(1-38) and Abeta(1-43) in addition to Abeta(1-40) and Abeta(1-42), in particular their behavior in mixtures representing the complex in vivo Abeta pool. We demonstrate that Abeta(1-38) and Abeta(1-43) aggregate similar to Abeta(1-40) and Abeta(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 Abeta, Abeta(1-38) and Abeta(1-43) significantly affect the behaviors of Abeta(1-40) and Abeta(1-42). The short timescale conformational flexibility of Abeta(1-38) is suggested to be responsible for enhancing toxicity of Abeta(1-40) while exerting a cyto-protective effect on Abeta(1-42). Our results indicate that the complex in vivo Abeta peptide array and variations thereof is critical in Alzheimer disease, which can influence the selection of current and new therapeutic strategies.