Dramatic Aggregation of Alzheimer Aβ by Cu(II) Is Induced by Conditions Representing Physiological Acidosis

• Published in: The Journal of biological chemistry 1998-05, Vol.273 (21), p.12817-12826
• Main Authors: Atwood, Craig S., Moir, Robert D., Huang, Xudong, Scarpa, Richard C., Bacarra, N. Michael E., Romano, Donna M., Hartshorn, Mariana A., Tanzi, Rudolph E., Bush, Ashley I.
• Format: Article
• Language: English
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.273.21.12817

The cortical deposition of Aβ is an event that occurs in Alzheimer's disease, Down's syndrome, head injury, and normal aging. Previously, in appraising the effects of different neurochemical factors that impact upon the solubility of Aβ, we observed that Zn2+ was the predominant bioessential metal to induce the aggregation of soluble Aβ at pH 7.4 in vitro and that this reaction is totally reversible with chelation. We now report that unlike other biometals tested at maximal biological concentrations, marked Cu2+-induced aggregation of Aβ1–40 emerged as the solution pH was lowered from 7.4 to 6.8 and that the reaction was completely reversible with either chelation or alkalinization. This interaction was comparable to the pH-dependent effect of Cu2+ on insulin aggregation but was not seen for aprotinin or albumin. Aβ1–40 bound three to four Cu2+ ions when precipitated at pH 7.0. Rapid, pH-sensitive aggregation occurred at low nanomolar concentrations of both Aβ1–40 and Aβ1–42 with submicromolar concentrations of Cu2+. Unlike Aβ1–40, Aβ1–42was precipitated by submicromolar Cu2+ concentrations at pH 7.4. Rat Aβ1–40 and histidine-modified human Aβ1–40 were not aggregated by Zn2+, Cu2+, or Fe3+, indicating that histidine residues are essential for metal-mediated Aβ assembly. These results indicate that H+-induced conformational changes unmask a metal-binding site on Aβ that mediates reversible assembly of the peptide. Since a mildly acidic environment together with increased Zn2+ and Cu2+ are common features of inflammation, we propose that Aβ aggregation by these factors may be a response to local injury. Cu2+, Zn2+, and Fe3+ association with Aβ explains the recently reported enrichment of these metal ions in amyloid plaques in Alzheimer's disease.