Zinc released from excited glutamatergic neurons accelerates amyloid β (Aβ) aggregation, underscoring the therapeutic potential of zinc chelation for the treatment of Alzheimer's disease (AD). Zinc can also alter A β concentration by affecting its degradation. In order to elucidate the possible role of zinc influx in secretase-processed A β production, SH-SY5Y cells stably expressing amyloid precursor protein (APP) were treated with pyrrolidine dithiocarbamate (PDTC), a zinc ionophore, and the resultant changes in APP processing were examined. PDTC decreased A β 40 and A β 42 concentrations in culture media bathing APP-expressing SH-SY5Y cells. Measuring the levels of a series of C-terminal APP fragments generated by enzymatic cutting at different APP-cleavage sites showed that both β-and α-cleavage of APP were inhibited by zinc influx. PDTC also interfered with the maturation of APP. PDTC, however, paradoxically increased the intracellular levels of A β 40. These results indicate that inhibition of secretase-mediated APP cleavage accounts-at least in part- for zinc inhibition of A β secretion.
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