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

Terman, Alexi (author): Karolinska Institutet,Karolinska University Hospital, Stockholm

Hallbeck, Martin (author): Östergötlands Läns Landsting,Linköpings universitet,Experimentell patologi,Hälsouniversitetet,Klinisk patologi och klinisk genetik

Kågedal, Katarina (author): Linköpings universitet,Experimentell patologi,Hälsouniversitetet

Marcusson, Jan (author): Östergötlands Läns Landsting,Linköpings universitet,Geriatrik,Hälsouniversitetet,Geriatriska kliniken

(creator_code:org_t)

2014-10-28
2011
English.
In: Autophagy. - : Landes Bioscience. - 1554-8627 .- 1554-8635. ; 7:12, s. 1528-1545

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Abstract Subject headings

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.

By the author/editor: Zheng, Lin; Terman, Alexi; Hallbeck, Martin; Dehvari, Nodi; Cowburn, Richard ...; Benedikz, Eiriku ...; show more...; Kågedal, Katarin ...; Cedazo-Minguez, ...; Marcusson, Jan; show less...

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