Document Detail

Copper-mediated amyloid-beta toxicity is associated with an intermolecular histidine bridge.
MedLine Citation:
PMID:  16595673     Owner:  NLM     Status:  MEDLINE    
Amyloid-beta peptide (Abeta) is pivotal to the pathogenesis of Alzheimer disease. Here we report the formation of a toxic Abeta-Cu2+ complex formed via a histidine-bridged dimer, as observed at Cu2+/peptide ratios of >0.6:1 by EPR spectroscopy. The toxicity of the Abeta-Cu2+ complex to cultured primary cortical neurons was attenuated when either the pi -or tau-nitrogen of the imidazole side chains of His were methylated, thereby inhibiting formation of the His bridge. Toxicity did not correlate with the ability to form amyloid or perturb the acyl-chain region of a lipid membrane as measured by diphenyl-1,3,5-hexatriene anisotropy, but did correlate with lipid peroxidation and dityrosine formation. 31P magic angle spinning solid-state NMR showed that Abeta and Abeta-Cu2+ complexes interacted at the surface of a lipid membrane. These findings indicate that the generation of the Abeta toxic species is modulated by the Cu2+ concentration and the ability to form an intermolecular His bridge.
David P Smith; Danielle G Smith; Cyril C Curtain; John F Boas; John R Pilbrow; Giuseppe D Ciccotosto; Tong-Lay Lau; Deborah J Tew; Keyla Perez; John D Wade; Ashley I Bush; Simon C Drew; Frances Separovic; Colin L Masters; Roberto Cappai; Kevin J Barnham
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Publication Detail:
Type:  In Vitro; Journal Article; Research Support, Non-U.S. Gov't     Date:  2006-04-04
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  281     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2006 Jun 
Date Detail:
Created Date:  2006-05-29     Completed Date:  2006-08-07     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  15145-54     Citation Subset:  IM    
Department of Pathology, Centre for Neuroscience, and School of Chemistry, University of Melbourne, Victoria 3010, Australia.
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MeSH Terms
Amyloid beta-Protein / chemistry,  metabolism*,  toxicity*
Cells, Cultured
Copper / chemistry,  metabolism*,  toxicity*
Electron Spin Resonance Spectroscopy
Histidine / chemistry
Molecular Structure
Neurons / drug effects,  metabolism
Nuclear Magnetic Resonance, Biomolecular
Peptide Fragments / chemistry,  metabolism,  toxicity
Reg. No./Substance:
0/Amyloid beta-Protein; 0/Peptide Fragments; 71-00-1/Histidine; 7440-50-8/Copper

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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