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Evidence of fibril-like β-sheet structures in a neurotoxic amyloid intermediate of Alzheimer's β-amyloid

Nature Structural & Molecular Biology volume 14, pages 11571164 (2007) | Download Citation

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Abstract

Diffusible subfibrillar aggregates of amyloid proteins are potent neurotoxins and primary suspects in amyloid diseases including Alzheimer's disease. Despite widespread interest, the molecular structures of the amyloid intermediates and the conformational conversions in amyloid misfolding are poorly understood. Here we present a molecular-level examination of sequence-specific secondary structures and supramolecular structures of a neurotoxic amyloid intermediate of the 40-residue β-amyloid (Aβ) peptide involved in Alzheimer's disease. Using solid-state NMR and electron microscopy, we show that, before fibrillization, natively unstructured monomeric Aβ is subject to large conformational changes into a spherical amyloid intermediate of 15–35 nm diameter, which has predominantly parallel β-sheet structures. Structural comparison with Aβ fibrils demonstrates that formation of this β-sheet intermediate (Iβ) largely defines conformational transitions in amyloid misfolding. Neurotoxicity assays on PC12 cells show that Iβ shows higher toxicity than the fibril, indicating that the β-sheet formation may trigger neurotoxicity.

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Acknowledgements

We thank M. Rasenick and J.-Z. Yu (University of Illinois at Chicago) for the PC-12 cells; L. Juarez and B. Lee for assistance with TEM studies and peptide synthesis, respectively; C. Bhardwaj, W. Cho and members of his group, and G. Fenteany for assistance with the neurotoxicity assay; R. Tycko for the structural model of Aβ1–40 used in Fig. 4b and C. Jameson, T. Keiderling and W. Klein for suggestions. This work was supported in part by the Alzheimer's Association (NIRG 035123), the Dreyfus Foundation Teacher-Scholar Award program, the US National Science Foundation CAREER program (CHE 449952), and the National Institutes of Health RO1 program (AG028490).

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  1. Department of Chemistry, University of Illinois at Chicago, Chicago, Illinois 60607, USA.

    • Sandra Chimon
    • , Medhat A Shaibat
    • , Christopher R Jones
    • , Diana C Calero
    • , Buzulagu Aizezi
    •  & Yoshitaka Ishii

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Correspondence to Yoshitaka Ishii.

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https://doi.org/10.1038/nsmb1345

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