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Elsevier, Journal of Biological Chemistry, 44(287), p. 36732-36743, 2012

DOI: 10.1074/jbc.m112.394635

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

Journal article published in 2012 by Annelies Vandersteen, Masman Mf, Marcelo F. Masman, Greet De Baets, Wim Jonckheere, Kees van der Werf, K. Van Der Werf, Siewert J. Marrink, Marrink Sj, Jef Rozenski ORCID, Iryna Benilova, Bart De Strooper, Vinod Subramaniam, Joost Schymkowitz, Frederic Rousseau and other authors.
This paper is made freely available by the publisher.
This paper is made freely available by the publisher.

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Abstract

Current therapeutic approaches under development for Alzheimer disease, including γ-secretase modulating therapy, aim at increasing the production of Aβ(1-38) and Aβ(1-40) at the cost of longer Aβ peptides. Here, we consider the aggregation of Aβ(1-38) and Aβ(1-43) in addition to Aβ(1-40) and Aβ(1-42), in particular their behavior in mixtures representing the complex in vivo Aβ pool. We demonstrate that Aβ(1-38) and Aβ(1-43) aggregate similar to Aβ(1-40) and Aβ(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 Aβ, Aβ(1-38) and Aβ(1-43) significantly affect the behaviors of Aβ(1-40) and Aβ(1-42). The short timescale conformational flexibility of Aβ(1-38) is suggested to be responsible for enhancing toxicity of Aβ(1-40) while exerting a cyto-protective effect on Aβ(1-42). 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.