Characterization of copper interactions with Alzheimer amyloid beta peptides: Identification of an attomolar-affinity copper binding site on amyloid beta 1-42

Citation
Cs. Atwood et al., Characterization of copper interactions with Alzheimer amyloid beta peptides: Identification of an attomolar-affinity copper binding site on amyloid beta 1-42, J NEUROCHEM, 75(3), 2000, pp. 1219-1233
Citations number
50
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Neurosciences & Behavoir
Journal title
JOURNAL OF NEUROCHEMISTRY
ISSN journal
0022-3042 → ACNP
Volume
75
Issue
3
Year of publication
2000
Pages
1219 - 1233
Database
ISI
SICI code
0022-3042(200009)75:3<1219:COCIWA>2.0.ZU;2-Q
Abstract
Cu and Zn have been shown to accumulate in the brains of Alzheimer's diseas e patients. We have previously reported that Cu2+ and Zn2+ bind amyloid bet a (A beta), explaining their enrichment in plaque pathology. Here we detail the stoichiometries and binding affinities of multiple cooperative Cu2+-bi nding sites on synthetic A beta 1-40 and A beta 1-42. We have developed a l igand displacement technique (competitive metal capture analysis) that uses metal-chelator complexes to evaluate metal ion binding to A beta, a notori ously self-aggregating peptide. This analysis indicated that there is a ver y-high-affinity Cu2+-binding site on A beta 1-42 (log K-app = 17.2) that me diates peptide precipitation and that the tendency of this peptide to self- aggregate in aqueous solutions is due to the presence of trace Cu2+ contami nation (customarily similar to 0.1 mu M). In contrast, A beta 1-40 has much lower affinity for Cu2+ at this site (estimated log K-app = 10.3), explain ing why this peptide is less self-aggregating. The greater Cu2+-binding aff inity of A beta 1-42 compared with A beta 1-40 is associated with significa ntly diminished negative cooperativity, The role of trace metal contaminati on in inducing A beta precipitation was confirmed by the demonstration that A beta peptide (10 mu M) remained soluble for 5 days only in the presence of high-affinity Cu2+-selective chelators.