Histidine-13 is a crucial residue in the zinc ion-induced aggregation of the Aβ peptide of Alzheimer's disease

Metal ions such as Zn2+ and Cu2+ have been implicated in both the aggregation and neurotoxicity of the beta-amyloid (A beta) peptide that is present in the brains of Alzheimer's sufferers. Zinc ions in particular have been shown to induce rapid aggregation of A beta. Rat A beta binds zinc ions much less avidly than human A beta, and rats do not form cerebral A beta amyloid. Rat A beta differs from human A beta 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 A beta, rat A beta, 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 Zn2+-induced aggregation behavior of rat and human A beta. The coordination of Zn2+ to histidine-13 is critical to the zinc ion induced aggregation of A beta.