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Title: Cu K-edge X-ray Absorption Spectroscopy Reveals Differential Copper Coordimation Within Amyloid-beta Oligomers Compared to Amyloid-beta Monomers

The fatal neurodegenerative disorder Alzheimer's disease (AD) has been linked to the formation of soluble neurotoxic oligomers of amyloid-{beta} (A{beta}) peptides. These peptides have high affinities for copper cations. Despite their potential importance in AD neurodegeneration few studies have focused on probing the Cu{sup 2+/1+} coordination environment within A{beta} oligomers. Herein we present a Cu K-edge X-ray absorption spectroscopic study probing the copper-coordination environment within oligomers of A{beta}(42) (sequence: DAEFRHDSGYEVHHQKLVFFAEDVGSNKGAIIGLMVGGVVIA). We find that the Cu{sup 2+} cation is contained within a square planar mixed N/O ligand environment within A{beta}(42) oligomers, which is similar to the copper coordination environment of the monomeric forms of {l_brace}Cu{sup II}A{beta}(40){r_brace} and {l_brace}Cu{sup II}A{beta}(16){r_brace}. Reduction of the Cu{sup 2+} cation within the A{beta}(42) oligomers to Cu{sup 1+} yields a highly dioxygen sensitive copper-species that contains Cu{sup 1+} in a tetrahedral coordination geometry. This can be contrasted with monomers of {l_brace}Cu{sup I}A{beta}(40){r_brace} and {l_brace}Cu{sup I}A{beta}(16){r_brace}, which contain copper in a dioxygen inert linear bis-histidine ligand environment [Shearer and Szalai, J. Am. Chem. Soc., 2008, 130, 17826]. The biological implications of these findings are discussed.
Authors:
; ; ;
Publication Date:
OSTI Identifier:
1041826
Report Number(s):
BNL--97504-2012-JA
TRN: US201212%%238
DOE Contract Number:
DE-AC02-98CH10886
Resource Type:
Journal Article
Resource Relation:
Journal Name: Chemical Communications; Journal Volume: 46
Research Org:
BROOKHAVEN NATIONAL LABORATORY (BNL)
Sponsoring Org:
USDOE SC OFFICE OF SCIENCE (SC)
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; ABSORPTION SPECTROSCOPY; CATIONS; COPPER; NERVOUS SYSTEM DISEASES; LIGANDS; MONOMERS; PEPTIDES; REDUCTION