Article abstract
Nature Structural & Molecular Biology 14, 1157 - 1164 (2007)
Published online: 2 December 2007 | doi:10.1038/nsmb1345
Evidence of fibril-like 
-sheet structures in a neurotoxic amyloid intermediate of Alzheimer's -amyloid
Sandra Chimon1, Medhat A Shaibat1, Christopher R Jones1, Diana C Calero1, Buzulagu Aizezi1 & Yoshitaka Ishii1
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 
-amyloid (A) peptide involved in Alzheimer's disease. Using solid-state NMR and electron microscopy, we show that, before fibrillization, natively unstructured monomeric A is subject to large conformational changes into a spherical amyloid intermediate of 15–35 nm diameter, which has predominantly parallel -sheet structures. Structural comparison with A fibrils demonstrates that formation of this -sheet intermediate (I
) largely defines conformational transitions in amyloid misfolding. Neurotoxicity assays on PC12 cells show that I shows higher toxicity than the fibril, indicating that the -sheet formation may trigger neurotoxicity.
- Department of Chemistry, University of Illinois at Chicago, Chicago, Illinois 60607, USA.
Correspondence to: Yoshitaka Ishii1 e-mail: yishii@uic.edu
MORE ARTICLES LIKE THIS
These links to content published by NPG are automatically generated.
NEWS AND VIEWS
Medicine Danger ? misfolding proteinsNature News and Views (04 Apr 2002)
α-synuclein and cytosolic dopamine: Stabilizing a bad situationNature Medicine News and Views (01 Dec 2001)
See all 4 matches for News And ViewsRESEARCH
EGCG redirects amyloidogenic polypeptides into unstructured, off-pathway oligomersNature structural & molecular biology Article (01 Jun 2008)
Hsp70 and Hsp40 attenuate formation of spherical and annular polyglutamine oligomers by partitioning monomerNature Structural & Molecular Biology Article (01 Dec 2004)
See all 48 matches for Research
