INHIBITION OF BETA-AMYLOID PRODUCTION BY ACTIVATION OF PROTEIN-KINASE-C

The cellular factors regulating the generation of beta-amyloid from th e amyloid precursor protein (APP) are unknown. Activation of protein k inase C (PKC) by phorbol ester treatment inhibited the generation of t he 4-kDa beta-amyloid peptide in transfected COS cells, a human glioma cell line, and human cortical astrocytes. An analogue of diacylglycer ol, the endogenous cellular activator of PKC, also inhibited the gener ation of beta-amyloid. Activation of PKC increased the level of secret ed APP in transfected COS cells but did not significantly affect the l evel of secreted APP in primary human astrocytes or in the glioma cell line. Cell-associated APP and the secreted APP derivative, but not be ta-amyloid, were phosphorylated on serine residues. Activation of PKC did not increase the level of APP phosphorylation, suggesting that PKC modulates the proteolytic cleavage of APP indirectly by phosphorylati on of other substrates. These results indicate that PKC activation inh ibits beta-amyloid production by altering APP processing and suggest t hat beta-amyloid production can be regulated by the phospholipase C-di acylglycerol signal transduction pathway.