Macroautophagy-generated increase of lysosomal amyloid β-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 β-protein (Aβ) 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 Aβ 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 Aβ monomers and oligomers, (2) increased reactive oxygen species production, and (3) enhanced apoptosis. Oxidant-induced apoptosis positively correlated with cellular Aβ production, being the highest in cells that were stably transfected with APP Swedish KM670/671NL double mutation. Inhibition of γ-secretase, prior and/or in parallel to hyperoxia, suggested that the increase of lysosomal Aβ 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 Aβ accumulation are essential for oxidant-induced apoptosis in cultured neuroblastoma cells and provide aditional support for the interactive role of oxidative stress and the lysosomal system in AD-related neurodegeneration.
Place, publisher, year, edition, pages
Landes Bioscience , 2011. Vol. 7, no 12, 1528-1545 p.
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:liu:diva-72778DOI: 10.4161/auto.7.12.18051ISI: 000298182600012OAI: oai:DiVA.org:liu-72778DiVA: diva2:462421
Funding agencies|Gustav V and Queen Victoria Foundation||County Council of Ostergotland||Stiftelsen Olle Engkvist Byggmastare||Stifielsen for Gamla Tjanarinnor||Gunoch Bertil Stohnes Stiftelse||Lions forskningsfond||Svenska Lundbeckstiftelsen||Karolinska Institute Fund for Geriatric Research||Alice och Knut Wallenberg Stiftelse||Swedish Alzheimer Foundation||Swedish Brain Power||2011-12-072011-12-072012-01-23Bibliographically approved