Oxidative stress promotes JNK-dependent amyloidogenic processing of normally expressed human APP by differential modification of α-, β- and γ-secretase expression

The pathogenesis of Alzheimer disease (AD) is complex and is certain to involve diverse etiological factors, but a central role has been strongly suggested for amyloid β-protein (Aβ), based on genetic, biochemical and neurotoxicological evidence. In contrast with the well-documented effect of genetic mutations in Aβ overproduction, not much is known about the mechanisms involved in sporadic AD (SAD) which account for more than 95% of cases. Extensive data from patients and in vivo animal models indicate that oxidative stress is one of the cardinal factors most frequently associated with this neurodegenerative disease. The aim of the present study was to explore the effect of oxidative stress on the normally expressed wild-type amyloid precursor protein (APP) in human neuroblastoma cells, which represents a more physiological model of neuronal Aβ generation. Since H2O2 is the main source of the highly reactive hydroxyl radical in the brain, and FeCl2 can stimulate oxidative stress, including the formation of the hydroxyl radical from H2O2, in the present work we studied the effect of these two pro-oxidant molecules on the levels and processing of human APP by α-, β- and γ-secretase, and the role of the stress-activated kinase c-jun N-terminal kinase (JNK). We provide evidence for a dual modulation of amyloid precursor protein metabolism in differentiated human neuroblastoma cells related with a down-regulation of α-secretase and up-regulation of γ-secretase, and particularly of β-secretase and also a JNK depending Aβ generation.