Protein kinase C epsilon suppresses A beta production and promotes activation of alpha-secretase

Deposition of plaques containing A beta is considered important in the path ogenesis of Alzheimer's disease. Phorbol esters that activate protein kinas e C (PKC) promote alpha -secretase-mediated processing of the beta amyloid precursor protein (APP), which generally reduces formation of A beta. To de termine which PKC isozymes mediate this process, we studied CHO cells that express human APP(751). Phorbol 12-myristate, 13-acetate (PMA)-stimulated A PP secretion, which was reduced by a general PKC inhibitor bisindoylmaleimi de I, but not by Go 6976, which inhibits PKC alpha, beta, gamma, and mu. Si nce PKC delta and epsilon were the only other PMA-sensitive isozymes presen t, we studied cells that express selective peptide inhibitors of these isoz ymes. Expression of the PKC epsilon inhibitor inhibited PMA-induced APPs se cretion and suppression of A beta production. In contrast, the PKC delta in hibitor had no effect. These results provide evidence that PKC epsilon decr eases A beta production by promoting alpha -secretase mediated cleavage of APP. (C) 2001 Academic Press.