Macroautophagy-generated increase of lysosomal amyloid beta-protein mediates oxidant-induced apoptosis of cultured neuroblastoma cells
2011 (English)In: Autophagy, ISSN 1554-8627, Vol. 7, no 12, 1528-1545 p.Article in journal (Refereed) Published
Increasing evidence suggests the toxicity of intracellular amyloid beta-protein (A beta) to neurons, as well as the involvement of oxidative stress in Alzheimer disease (AD). Here we show that normobaric hyperoxia (exposure of cells to 400/c oxygen for five days, and consequent activation of macroautophagy and accumulation of A beta 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 beta monomers and oligomers, (2) increased reactive oxygen species production, and (3) enhanced apoptosis. Oxidant-induced apoptosis positively correlated with cellular A beta production, being the highest in cells that were stably transfected with APP Swedish KM670/671NL double mutation. Inhibition of v-secretase, prior and/or in parallel to hyperoxia, suggested that the increase of lysosomal A beta 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 beta 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.
Place, publisher, year, edition, pages
2011. Vol. 7, no 12, 1528-1545 p.
Alzheimer disease, amyloid beta-protein, amyloid precursor protein, apoptosis, autophagy, lysosomes, oxidative stress
IdentifiersURN: urn:nbn:se:su:diva-71156DOI: 10.4161/auto.7.12.18051ISI: 000298182600012OAI: oai:DiVA.org:su-71156DiVA: diva2:483889
authorCount :92012-01-262012-01-262012-01-26Bibliographically approved