ISSN:
1471-4159
Source:
Blackwell Publishing Journal Backfiles 1879-2005
Topics:
Medicine
Notes:
Abstract: Cu and Zn have been shown to accumulate in the brains of Alzheimer's disease patients. We have previously reported that Cu2+ and Zn2+ bind amyloid β (Aβ), explaining their enrichment in plaque pathology. Here we detail the stoichiometries and binding affinities of multiple cooperative Cu2+-binding sites on synthetic Aβ1-40 and Aβ1-42. We have developed a ligand displacement technique (competitive metal capture analysis) that uses metal-chelator complexes to evaluate metal ion binding to Aβ, a notoriously self-aggregating peptide. This analysis indicated that there is a very-high-affinity Cu2+-binding site on Aβ1-42 (log Kapp = 17.2) that mediates peptide precipitation and that the tendency of this peptide to self-aggregate in aqueous solutions is due to the presence of trace Cu2+ contamination (customarily ∼0.1 μM). In contrast, Aβ1-40 has much lower affinity for Cu2+ at this site (estimated log Kapp = 10.3), explaining why this peptide is less self-aggregating. The greater Cu2+-binding affinity of Aβ1-42 compared with Aβ1-40 is associated with significantly diminished negative cooperativity. The role of trace metal contamination in inducing Aβ precipitation was confirmed by the demonstration that Aβ peptide (10 μM) remained soluble for 5 days only in the presence of high-affinity Cu2+-selective chelators.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1046/j.1471-4159.2000.0751219.x
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