Deposition of plaques containing A beta is considered important in the pathogenesis of Alzheimer's disease. Phorbol esters that activate protein kinase C (PKC) promote alpha -secretase-mediated processing of the beta amyloid precursor protein (APP), which generally reduces formation of A beta. To determine which PKC isozymes mediate this process, we studied CHO cells that express human APP(751). Phorbol 12-myristate, 13-acetate (PMA)-stimulated APP secretion, which was reduced by a general PKC inhibitor bisindoylmaleimide I, but not by Go 6976, which inhibits PKC alpha, beta, gamma, and mu. Since PKC delta and epsilon were the only other PMA-sensitive isozymes present, we studied cells that express selective peptide inhibitors of these isozymes. Expression of the PKC epsilon inhibitor inhibited PMA-induced APPs secretion and suppression of A beta production. In contrast, the PKC delta inhibitor had no effect. These results provide evidence that PKC epsilon decreases A beta production by promoting alpha -secretase mediated cleavage of APP.