期刊
AUTOPHAGY
卷 7, 期 12, 页码 1528-1545出版社
TAYLOR & FRANCIS INC
DOI: 10.4161/auto.7.12.18051
关键词
Alzheimer disease; amyloid beta-protein; amyloid precursor protein; apoptosis; autophagy; lysosomes; oxidative stress
类别
资金
- 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
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.
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