MODULATION OF A-BETA ADHESIVENESS AND SECRETASE SITE CLEAVAGE BY ZINC

Abnormalities of zinc homeostasis occur in Alzheimer's disease (AD), a dementia characterized by the aggregation of A beta in the brain, and in Down syndrome, a condition characterized by premature AD, We studi ed the binding of Zn2+ to a synthetic peptide representing residues 1- 40 (A beta(1-40)), as well as other domains of A beta. Two classes of Zn2+ binding were identified by Zn-65(2+) labeling: highly specific pH -dependent high affinity (K-alpha = 107 nM) binding, and lower affinit y (K-alpha = 5.2 mu M) binding. Gel filtration chromatography identifi ed monomeric, dimeric, and polymeric A beta species. Zinc induced a ma rked loss of A beta solubility upon chromatographic analysis. This was attributed to precipitation onto the column glass, which contains alu minosilicate, and was confirmed by the observation of zinc-accelerated precipitation of A beta by kaolin, a hydrated aluminum silicate suspe nsion. Zinc binding also increased A beta resistance to tryptic cleava ge at the secretase site, indicating that a small (<3 mu M) increase i n brain Zn2+ 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. Consequentl y, abnormalities of regional zinc concentrations in the brains of pati ents with AD or Down syndrome may contribute to A beta amyloidosis in these disorders.