Metal ions such as Zn(2+) and Cu(2+) have been implicated in both the aggregation and neurotoxicity of the beta-amyloid (Abeta) peptide that is present in the brains of Alzheimer's sufferers. Zinc ions in particular have been shown to induce rapid aggregation of Abeta. Rat Abeta binds zinc ions much less avidly than human Abeta, and rats do not form cerebral Abeta amyloid. Rat Abeta differs from human Abeta by the substitution of Gly for Arg, Phe for Tyr, and Arg for His at positions 5, 10, and 13, respectively. Through the use of synthetic peptides corresponding to the first 28 residues of human Abeta, rat Abeta, and single-residue variations, we use circular dichroism spectroscopy, sedimentation assays, and immobilized metal ion affinity chromatography to show that the substitution of Arg for His-13 is responsible for the different Zn(2+)-induced aggregation behavior of rat and human Abeta. The coordination of Zn(2+) to histidine-13 is critical to the zinc ion induced aggregation of Abeta.