Amyloid beta-protein (A beta) aggregation produces an oxidative stress in neuronal cells that, in turn, may induce an amyloidogenic shift of neuronal metabolism. To investigate this hypothesis, we analyzed intra-and extracellular A beta content in NT2 differentiated cells incubated with 4-hydroxy-2,3-nonenal (HNE), a major product of lipid peroxidation. In parallel, we evaluated protein kinase C (PKC) isoenzymes activity, a signaling system suspected to modulate amyloid precursor protein (APP) processing, Low HNE concentrations (0.1-1 mu M) induced a 2-6 fold increase of intracellular AP production that was concomitant with selective activation of beta I and beta II PKC isoforms, without affecting either cell viability or APP full-length expression. Selective activation of the same PKC isoforms was observed following NT2 differentiation. Our findings suggest that PKC beta isoenzymes are part of cellular mechanisms that regulate production of the intracellular A beta pool. Moreover, they indicate that lipid peroxidation fosters intracellular A beta accumulation, creating a vicious neurodegenerative loop.