title: Molecular plasticity regulates oligomerization and cytotoxicity of the multipeptide-length amyloid-β peptide pool.
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.
authors.affiliation: Switch Laboratory, Flanders Institute for Biotechnology (VIB), B-3000 Leuven, Belgium.
authors.forename: Annelies
authors.initials: A
authors.lastname: Vandersteen
authors.forename: Marcelo F
authors.initials: MF
authors.lastname: Masman
authors.forename: Greet
authors.initials: G
authors.lastname: De Baets
authors.forename: Wim
authors.initials: W
authors.lastname: Jonckheere
authors.forename: Kees
authors.initials: K
authors.lastname: van der Werf
authors.forename: Siewert J
authors.initials: SJ
authors.lastname: Marrink
authors.forename: Jef
authors.initials: J
authors.lastname: Rozenski
authors.forename: Iryna
authors.initials: I
authors.lastname: Benilova
authors.forename: Bart
authors.initials: B
authors.lastname: De Strooper
authors.forename: Vinod
authors.initials: V
authors.lastname: Subramaniam
authors.forename: Joost
authors.initials: J
authors.lastname: Schymkowitz
authors.forename: Frederic
authors.initials: F
authors.lastname: Rousseau
authors.forename: Kerensa
authors.initials: K
authors.lastname: Broersen
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D020816:Amino Acid Motifs; D000682:Amyloid / Q000494:pharmacology / Q000502:physiology* / Q000648:ultrastructure; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000494:pharmacology / Q000502:physiology; D052160:Benzothiazoles; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D005456:Fluorescent Dyes / Q000737:chemistry; D006801:Humans; D007700:Kinetics; D018625:Microscopy, Atomic Force; D010446:Peptide Fragments / Q000737:chemistry* / Q000494:pharmacology / Q000502:physiology; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D013844:Thiazoles / Q000737:chemistry
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D052160:Benzothiazoles; D005456:Fluorescent Dyes; D010446:Peptide Fragments; D013844:Thiazoles; C009462:thioflavin T