Nat Struct Mol Biol. 2015 May 4. doi: 10.1038/nsmb.2991. [Epub ahead of print]
Aβ(1-42) fibril structure illuminates self-recognition and replication of amyloid in Alzheimer's disease.
- 1Department of Chemistry, University of Illinois at Chicago, Chicago, Illinois, USA.
- 2Cancer and Inflammation Program, Leidos Biomedical Research, National Cancer Institute at Frederick, Frederick, Maryland, USA.
- 31] Institute of Biomedical Research and Innovation, Kobe, Japan.  Department of Anatomy and Developmental Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
- 41] Cancer and Inflammation Program, Leidos Biomedical Research, National Cancer Institute at Frederick, Frederick, Maryland, USA.  Sackler Institute of Molecular Medicine, Department of Human Genetics and Molecular Medicine, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
- 51] Department of Chemistry, University of Illinois at Chicago, Chicago, Illinois, USA.  Center for Structural Biology, University of Illinois at Chicago, Chicago, Illinois, USA.
Increasing evidence has suggested that formation and propagation of misfolded aggregates of 42-residue human amyloid β (Aβ(1-42)), rather than of the more abundant Aβ(1-40), provokes the Alzheimer's disease cascade. However, structural details of misfolded Aβ(1-42) have remained elusive. Here we present the atomic model of an Aβ(1-42) amyloid fibril, from solid-state NMR (ssNMR) data. It displays triple parallel-β-sheet segments that differ from reported structures of Aβ(1-40) fibrils. Remarkably, Aβ(1-40) is incompatible with the triple-β-motif, because seeding with Aβ(1-42) fibrils does not promote conversion of monomeric Aβ(1-40) into fibrils via cross-replication. ssNMR experiments suggest that C-terminal Ala42, absent in Aβ(1-40), forms a salt bridge with Lys28 to create a self-recognition molecular switch that excludes Aβ(1-40). The results provide insight into the Aβ(1-42)-selective self-replicating amyloid-propagation machinery in early-stage Alzheimer's disease.