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Nat Struct Mol Biol. 2015 Jun;22(6):499-505. doi: 10.1038/nsmb.2991. Epub 2015 May 4.

Aβ(1-42) fibril structure illuminates self-recognition and replication of amyloid in Alzheimer's disease.

Author information

1
Department of Chemistry, University of Illinois at Chicago, Chicago, Illinois, USA.
2
Cancer and Inflammation Program, Leidos Biomedical Research, National Cancer Institute at Frederick, Frederick, Maryland, USA.
3
1] Institute of Biomedical Research and Innovation, Kobe, Japan. [2] Department of Anatomy and Developmental Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
4
1] Cancer and Inflammation Program, Leidos Biomedical Research, National Cancer Institute at Frederick, Frederick, Maryland, USA. [2] Sackler Institute of Molecular Medicine, Department of Human Genetics and Molecular Medicine, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
5
1] Department of Chemistry, University of Illinois at Chicago, Chicago, Illinois, USA. [2] Center for Structural Biology, University of Illinois at Chicago, Chicago, Illinois, USA.

Abstract

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.

PMID:
25938662
PMCID:
PMC4476499
DOI:
10.1038/nsmb.2991
[Indexed for MEDLINE]
Free PMC Article

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