Whether zinc interacts with presenilin 1 (PS1), one of the causative genes of familial Alzheimer's disease (AD), is not known. Here we report that zinc modulates the synthesis of PSI. Exogenous zinc enhanced the amount of C-terminal fragments of PS1 (PS1-CTF) in neonatal mouse cortical cultures in a dose-dependent manner. Zinc also induced cell death in a dose-dependent manner. These effects of zinc were not mimicked by calcium, copper, or iron, and were blocked by a zinc-specific chelator, TPEN. Experiments using metabolic labeling and cycloheximide treatment revealed that zinc increased PS1-CTF by elevating the de novo synthesis of PS1. Time course experiments revealed that cell death commenced sooner (0.5-1 h) than enhancement of PS1-CTF (1-2 h) following zinc treatment. However, the amount of PS1-CTF remained unchanged during etoposide- or H2O2-induced cell death, suggesting that enhancement of PSI synthesis is specifically correlated with zinc-induced cell death.