Effect of pathogenic mutations on the structure and dynamics of Alzheimer's A beta 42-amyloid oligomers.
Converging lines of evidence suggest that soluble A beta-amyloid oligomers play a pivotal role in the pathogenesis of Alzheimer's disease, and present direct effectors of synaptic and cognitive dysfunction. Three pathological E22-A beta-amyloid point mutants (E22G, E22K, E22Q) and the deletion mutant E22 Delta exhibit an enhanced tendency to form prefibrillar aggregates. The present study assessed the effect of these four mutations using molecular dynamics simulations and subsequent structural and energetic analyses. Our data shows that E22 plays a unique role in wild type A beta, since it has a destabilising effect on the oligomer structure due to electrostatic repulsion between adjacent E22 side chains. Mutations in which E22 is replaced by an uncharged residue result in higher oligomer stability. This effect is also observed to a lesser extent for the E22K mutation and is consistent with its lower pathogenicity compared to other mutants. Interestingly, deletion of E22 does not destroy the amyloid fold but is compensated by local changes in the backbone geometry that allow the preservation of a structurally important salt bridge. The finding that all mutant oligomers investigated exhibit higher internal stability than the wild type offers an explanation for the experimentally observed enhanced oligomer formation and stability.
Kassler
Kristin
K
Bioinformatik, Institut für Biochemie, Friedrich-Alexander-Universität Erlangen-Nürnberg, Fahrstrasse 17, 91054, Erlangen, Germany.
Horn
Anselm H C
AH
Sticht
Heinrich
H
D000544:Alzheimer Disease / Q000235:genetics*; D000682:Amyloid / Q000235:genetics*; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry* / Q000235:genetics*; D006801:Humans; D056004:Molecular Dynamics Simulation; D009154:Mutation; D058255:Protease Nexins; D011956:Receptors, Cell Surface / Q000737:chemistry* / Q000235:genetics*
D000682:Amyloid; D016564:Amyloid beta-Protein Precursor; D058255:Protease Nexins; D011956:Receptors, Cell Surface