2012| September

Authors:

Annelies Vandersteen, Marcelo Fabricio Masman, Greet De

Baets, Wim Jonckheere, Kees van der Werf, Siewert Jan Marrink, Jef

Rozenski, Iryna Benilova, Bart De Strooper, Vinod Subramaniam, Joost

Schymkowitz, Frederic Rousseau, Kerensa Broersen

Title:

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

Abstract:

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.

DOI: 10.1074/jbc.M112.394635