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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 Aβ_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 alkalinization. This interaction was comparable to the pH-dependent effect of Cu²⁺ on insulin aggregation but was not seen for aprotinin or albumin. Aβ_1–40 bound three to four Cu²⁺ ions when precipitated at pH 7.0. Rapid, pH-sensitive aggregation …