Abnormalities of zinc homeostasis occur in Alzheimer's disease (AD), a dementia characterized by the aggregation of AP in the brain, and in Down syndrome, a condition characterized by premature AD. We studied the binding of Zn-2+ to a synthetic peptide representing residues 1-40 (A-beta-1-40), as well as other domains of A-beta. Two classes of Zn-2+ binding were identified by 65Zn-2+ labeling: highly specific pH-dependent high affinity (K-a = 107 nM) binding, and lower affinity (K-a = 5.2 mu-M) binding. Gel filtration chromatography identified monomeric, dimeric, and polymeric A-beta species. Zinc induced a marked loss of A-beta solubility upon chromatographic analysis. This was attributed to precipitation onto the column glass, which contains aluminosilicate, and was confirmed by the observation of zinc-accelerated precipitation of A-beta by kaolin, a hydrated aluminum silicate suspension. Zinc binding also increased A-beta resistance to tryptic cleavage at the secretase site, indicating that a small (lt 3 mu-M) increase in brain Zn-2+ concentration could significantly alter A-beta metabolism. We propose that elevated brain interstitial zinc levels may increase A-beta adhesiveness and interfere with A-beta catabolism. Consequently, abnormalities of regional zinc concentrations in the brains of patients with AD or Down syndrome may contribute to A-beta amyloidosis in these disorders.