Oxidative stress induces increase in intracellular amyloid beta-protein production and selective activation of beta I and beta II PKCs in NT2 cells

Amyloid beta-protein (A beta) aggregation produces an oxidative stress in n euronal cells that, in turn, may induce an amyloidogenic shift of neuronal metabolism. To investigate this hypothesis, we analyzed intra- and extracel lular A beta content in NT2 differentiated cells incubated with 4-hydroxy-2 ,3-nonenal (HNE), a major product of lipid peroxidation. In parallel, we ev aluated protein kinase C (PKC) isoenzymes activity, a signaling system susp ected to modulate amyloid precursor protein (APP) processing, Low HNE conce ntrations (0.1-1 mu M) induced a 2-6 fold increase of intracellular AP prod uction that was concomitant with selective activation of beta I and beta II PKC isoforms, without affecting either cell viability or APP full-length e xpression. Selective activation of the same PKC isoforms was observed follo wing 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 intrac ellular A beta accumulation, creating a vicious neurodegenerative loop. (C) 2000 Academic Press.