Macroautophagy-generated increase of lysosomal amyloid β-protein mediates oxidant-induced apoptosis of cultured neuroblastoma cells
| Autor: | Eirikur Benedikz, Angel Cedazo-Minguez, Katarina Kågedal, Martin Hallbeck, Richard F. Cowburn, Nodi Dehvari, Alexei Terman, Lin Zheng, Jan Marcusson |
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| Jazyk: | angličtina |
| Rok vydání: | 2011 |
| Předmět: |
Medicin och hälsovetenskap
Amyloid Cell Survival Intracellular Space Down-Regulation Apoptosis Tretinoin medicine.disease_cause Transfection Medical and Health Sciences Autophagy-Related Protein 5 Neuroblastoma Downregulation and upregulation Lysosomal-Associated Membrane Protein 2 medicine Amyloid precursor protein Autophagy Tumor Cells Cultured Humans RNA Small Interfering Molecular Biology chemistry.chemical_classification Cell Nucleus Reactive oxygen species Amyloid beta-Peptides biology Adenine Lysosome-Associated Membrane Glycoproteins Cell Differentiation Cell Biology medicine.disease Oxidants Cell biology Oxygen chemistry Vacuoles biology.protein Mutant Proteins Alzheimer's disease Amyloid Precursor Protein Secretases Lysosomes Reactive Oxygen Species Amyloid precursor protein secretase Research-Paper Microtubule-Associated Proteins Intracellular Oxidative stress |
| Zdroj: | Zheng, L, Terman, A, Hallbeck, M, Dehvari, N, Cowburn, R F, Benedikz, E, Kågedal, K, Cedazo-Minguez, A & Marcusson, J 2011, ' Macroautophagy-generated increase of lysosomal amyloid β-protein mediates oxidant-induced apoptosis of cultured neuroblastoma cells ', Autophagy, vol. 7, no. 12, pp. 1528-1545 . https://doi.org/10.4161/auto.7.12.18051 |
| Popis: | 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. 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 |
| Databáze: | OpenAIRE |
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