Oxidative stress induces intracellular accumulation of amyloid beta-protein (A beta) in human neuroblastoma cells

Several lines of evidence suggest that enhanced oxidative stress is involve d in the pathogenesis and/or progression of Alzheimer's disease (AD). Amylo id beta-protein (A beta) that composes senile plaques, a major neuropatholo gical hallmark of AD, is considered to have a causal role in AD. Thus, we h ave studied the effect of oxidative stress on A beta metabolism within the cell. Here, we report that oxidative stress induced by H2O2 (100-250 mu M) caused an increase in the levels of intracellular A beta in human neuroblas toma SH-SY5Y cells. Treatment with 200 mu M H2O2 caused significant decreas es in the protein levels of full-length beta-amyloid precursor protein (APP ) and its COOH-terminal fragment that is generated by beta-cleavage, while the gene expression of APP was not altered under these conditions. A pulse- chase experiment further showed a decrease in the half-life of this amyloid ogenic COOH-terminal fragment but not in that of nonamyloidogenic counterpa rt in the H2O2-treated cells. These results suggest that oxidative stress p romotes intracellular accumulation of A beta through enhancing the amyloido genic pathway.