Lippincott Williams & Wilkins, Inc., Philadelphia
Characterization of Copper Interactions with Alzheimer Amyloid β Peptides
Identification of an Attomolar-Affinity Copper Binding Site on Amyloid β1-42
Article first published online: 22 SEP 2008
Journal of Neurochemistry
Volume 75, Issue 3, pages 1219–1233, September 2000
How to Cite
Atwood, C. S., Scarpa, R. C., Huang, X., Moir, R. D., Jones, W. D., Fairlie, D. P., Tanzi, R. E. and Bush, A. I. (2000), Characterization of Copper Interactions with Alzheimer Amyloid β Peptides. Journal of Neurochemistry, 75: 1219–1233. doi: 10.1046/j.1471-4159.2000.0751219.x
Drs. C. S. Atwood and R. C. Scarpa contributed equally to this article.
Abbreviations used: Aβ, amyloid β; AD, Alzheimer's disease; CDTA, trans-1,2-diaminocyclohexane-N,N,N′,N′-tetraacetic acid; CMCA, competitive metal capture analysis; DSA, dog serum albumin; DTPA, diethylenetriaminepentaacetic acid; PAGE, polyacrylamide gel electrophoresis; SDS, sodium dodecyl sulfate.
- Issue published online: 22 SEP 2008
- Article first published online: 22 SEP 2008
- Human amyloid β peptide;
- Alzheimer's disease;
- Binding affinity method;
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.