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

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

SUBMITTER: Vandersteen A 

PROVIDER: S-EPMC3481277 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature