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

Annelies Vandersteen, Marcelo F. Masman, Greet De Baets, Wim Jonckheere, Kees van der Werf, Siewert J. Marrink, Jef Rozenski, Iryna Benilova, Bart De Strooper, Vinod Subramaniam, Joost Schymkowitz, Frederic Rousseau, Kerensa Broersen*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

27 Citations (Scopus)
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Abstract

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.

Original languageEnglish
Pages (from-to)36732-36743
Number of pages12
JournalThe Journal of Biological Chemistry
Volume287
Issue number44
DOIs
Publication statusPublished - 19-Sep-2012

Keywords

  • Molecular Plasticity
  • γ-Secretase Modulating Therapy
  • Amyloid-β Peptide
  • Cytotoxicity
  • C-terminal Heterogeneity
  • Neurodegeneration
  • Biophysics
  • Amyloid
  • Alzheimer Disease
  • Aggregation

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