Abstract

Oligomeric and protofibrillar aggregates formed by the amyloid-beta peptide (Abeta) are believed to be involved in the pathology of Alzheimer's disease. Central to Alzheimer pathology is also the fact that the longer Abeta(42) peptide is more prone to aggregation than the more prevalent Abeta(40). Detailed structural studies of A beta oligomers and protofibrils have been impeded by aggregate heterogeneity and instability. We previously engineered a variant of Abeta that forms stable protofibrils and here we use solid-state NMR spectroscopy and molecular modeling to derive a structural model of these. NMR data are consistent with packing of residues 16 to 42 of Abeta protomers into hexameric barrel-like oligomers within the protofibril. The core of the oligomers consists of all residues of the central and C-terminal hydrophobic regions of Abeta, and hairpin loops extend from the core. The model accounts for why Abeta(42) forms oligomers and protofibrils more easily than Abeta(40).

Keywords

Alzheimer's disease; amyloid beta-peptides; neurotoxicity; oligomers; protein structures

Published in

Angewandte Chemie International Edition
2014, Volume: 53, number: 47, pages: 12756-12760
Publisher: WILEY-V C H VERLAG GMBH

SLU Authors

• Lendel, Christofer

  • The Department of Chemistry and Biotechnology, Swedish University of Agricultural Sciences
    

• Dubnovitsky, Anatoly

  • Karolinska Institute
  • The Department of Chemistry and Biotechnology, Swedish University of Agricultural Sciences
    

• Härd, Torleif

  • The Department of Chemistry and Biotechnology, Swedish University of Agricultural Sciences
    

UKÄ Subject classification

Structural Biology
Biophysics


Publication identifier

DOI: https://doi.org/10.1002/anie.201406357

Permanent link to this page (URI)

https://res.slu.se/id/publ/63511