Macroautophagy-generated increase of lysosomal amyloid ?-protein mediates oxidant-induced apoptosis of cultured neuroblastoma cells.

ABSTRACT: Increasing evidence suggests the toxicity of intracellular amyloid ?-protein (A?) to neurons, as well as the involvement of oxidative stress in Alzheimer disease (AD). Here we show that normobaric hyperoxia (exposure of cells to 40% oxygen for five days), and consequent activation of macroautophagy and accumulation of A? within lysosomes, induced apoptosis in differentiated SH-SY5Y neuroblastoma cells. Cells under hyperoxia showed: (1) increased numbers of autophagic vacuoles that contained amyloid precursor protein (APP) as well as A? monomers and oligomers, (2) increased reactive oxygen species production, and (3) enhanced apoptosis. Oxidant-induced apoptosis positively correlated with cellular A? production, being the highest in cells that were stably transfected with APP Swedish KM670/671NL double mutation. Inhibition of ?-secretase, prior and/or in parallel to hyperoxia, suggested that the increase of lysosomal A? resulted mainly from its autophagic uptake, but also from APP processing within autophagic vacuoles. The oxidative stress-mediated effects were prevented by macroautophagy inhibition using 3-methyladenine or ATG5 downregulation. Our results suggest that upregulation of macroautophagy and resulting lysosomal A? accumulation are essential for oxidant-induced apoptosis in cultured neuroblastoma cells and provide additional support for the interactive role of oxidative stress and the lysosomal system in AD-related neurodegeneration.

SUBMITTER: Zheng L 

PROVIDER: S-EPMC3288025 | biostudies-literature | 2011 Dec

REPOSITORIES: biostudies-literature