DRAMATIC AGGREGATION OF ALZHEIMER A-BETA BY CU(II) IS INDUCED BY CONDITIONS REPRESENTING PHYSIOLOGICAL ACIDOSIS

The cortical deposition of A beta 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 im pact upon the solubility of A beta, we observed that Zn2+ was the pred ominant bioessential metal to induce the aggregation of soluble A beta 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 A beta( 1-40) emerged as the solution pH was lowered from 7.4 to 6.8 and that the reaction was completely reversible with either chelation or alkali nization. This interaction was comparable to the pH-dependent effect o f Cu2+ On insulin aggregation but was not seen for aprotinin or albumi n. A beta(1-40) bound three to four Cu2+ ions when precipitated at pH 7.0. Rapid, pH-sensitive aggregation occurred at low nanomolar concent rations of both A beta(1-40) and A beta(1-42) with submicromolar conce ntrations of Cu2+. Unlike A beta(1-40) AP(1-42) was precipitated by su bmicromolar Cu2+ concentrations at pH 7.4, Rat A beta(1-40) and histid ine-modified human A beta(1-40) were not aggregated by Zn2+, Cu2+, Or Fe3+, indicating that histidine residues are essential for metal-media ted A beta assembly. These results indicate that H+-induced conformati onal changes unmask a metal-binding site on A beta that mediates rever sible assembly of the peptide. Since a mildly acidic environment toget her with increased Zn2+ and Cu2+ are common features of inflammation, we propose that AP aggregation by these factors may be a response to l ocal injury. Cu2+, Zn2+ and Fe3+ association with A beta explains the recently reported enrichment of these metal ions in amyloid plaques in Alzheimer's disease.