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

ABSTRACT: Increasing evidence has suggested that formation and propagation of misfolded aggregates of 42-residue human amyloid ? (A?(1-42)), rather than of the more abundant A?(1-40), provokes the Alzheimer's disease cascade. However, structural details of misfolded A?(1-42) have remained elusive. Here we present the atomic model of an A?(1-42) amyloid fibril, from solid-state NMR (ssNMR) data. It displays triple parallel-?-sheet segments that differ from reported structures of A?(1-40) fibrils. Remarkably, A?(1-40) is incompatible with the triple-?-motif, because seeding with A?(1-42) fibrils does not promote conversion of monomeric A?(1-40) into fibrils via cross-replication. ssNMR experiments suggest that C-terminal Ala42, absent in A?(1-40), forms a salt bridge with Lys28 to create a self-recognition molecular switch that excludes A?(1-40). The results provide insight into the A?(1-42)-selective self-replicating amyloid-propagation machinery in early-stage Alzheimer's disease.

SUBMITTER: Xiao Y

PROVIDER: S-EPMC4476499 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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

Xiao Yiling Y Ma Buyong B McElheny Dan D Parthasarathy Sudhakar S Long Fei F Hoshi Minako M Nussinov Ruth R Ishii Yoshitaka Y

Nature structural & molecular biology 20150504 6

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. Remarkabl ...[more]

PMID: 25938662

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Dataset Information

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

Publications

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

Similar Datasets

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