The cellular factors regulating the generation of beta A4 from the amyloid precursor protein (APP) are unknown. Protein phosphorylation by protein kinase C (PKC) has been found to influence the processing and metabolism of APP. In this report, we show that in the human neuroblastoma cell line SY5Y, beta A4 generation from full-length APP is not changed by PKC activation whereas production of the non-amyloidogenic secretory fragment (APPsec) and of the C-terminal fragment of beta A4 (p3) are stimulated. In addition, beta A4 generation from the membrane inserted C-terminal 100 residues (SPA4CT) of APP is stimulated by PKC activation. Accordingly attempts to divert APP processing from the amyloidogenic, beta A4-generating, to the non-amyloidogenic, secretory, pathway, have to address the nature and regulation of the two pathways and/or of the process leading to the cleavage of APP at the C-terminus of the beta A4 domain. The data reported here suggest that these mechanisms are cell-type specific.