Differential effects of zinc on amyloid precursor protein (APP) processingin copper-resistant variants of cultured Chinese hamster ovary cells

Previous studies have demonstrated that adding copper to Chinese-hamster ov ary (CHO) cells greatly reduced the levels of beta-amyloid (A beta) peptide in parental CHO-K1 and in copper resistant CHO-CUR3 cells which have lower intracellular copper levels. In the current study, zinc, the zinc chelator 1,10-phenanthroline or copper chelators bathocuproine and D-penicillamine were added to the culture media of stably transfected CHO cells. The data s how that zinc up to concentrations of 50 mu M or the presence of 1,10-phena nthroline specifically increased the level of secreted APP in CHO-K1 cells. By contrast, the level of secreted APP in CHO-CUR3 cells remained unaffect ed. APP holoprotein increased dramatically in CHO-CUR3 cells compared with CHO-K1 cells. The large decrease of A beta release seen in both cell lines at elevated extracellular zinc levels was due to specific inhibition of sec retion. These results indicate that a disturbed zinc-homeostasis may be an important factor influencing APP production, transport and processing.