Molecular plasticity regulates oligomerization and cytotoxicity of the multi-peptide length Aβ pool

Current therapeutic approaches under development for Alzheimer disease, including γ-secretase modulating therapy, aim at increasing the production of Aβ1-38 and Aβ1-40 at the cost of longer Aβ peptides. Here, we consider the aggregation of Aβ1-38 and Aβ1-43 in addition to Aβ1-40 and Aβ1-42; in particular their behavior in mixtures representing the complex in vivo Aβ pool. We demonstrate that Aβ1-38 and Aβ1-43 aggregate similar to Aβ1-40 and Aβ1-42, respectively, but display variation in kinetics of assembly and toxicity due to differences in short timescale conformational plasticity. In biologically relevant mixtures of Aβ, Aβ1-38 and Aβ1-43 significantly affect the behaviors of Aβ1-40 and Aβ1-42. The short timescale conformational flexibility of Aβ1-38 is suggested to be responsible for enhancing toxicity of Aβ1-40 whilst exerting a cyto-protective effect on Aβ1-42. Our results indicate that the complex in vivo Aβ peptide array, and variations thereof, is critical in Alzheimer disease, which can influence the selection of current and new therapeutic strategies.status: publishe