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Macroautophagy-generated increase of lysosomal amyloid β-protein mediates oxidant-induced apoptosis of cultured neuroblastoma cells
Linköping University, Department of Clinical and Experimental Medicine, Geriatric. Linköping University, Faculty of Health Sciences.
Karolinska University Hospital, Stockholm.
Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
Karolinska Institutet, Stockholm.
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2011 (English)In: Autophagy, ISSN 1554-8627, Vol. 7, no 12, 1528-1545 p.Article in journal (Refereed) Published
Abstract [en]

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.
National Category
Medical and Health Sciences
URN: urn:nbn:se:liu:diva-72778DOI: 10.4161/auto.7.12.18051ISI: 000298182600012OAI: 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||Available from: 2011-12-07 Created: 2011-12-07 Last updated: 2012-01-23Bibliographically approved
In thesis
1. Lysosomal Involvement in the Pathogenesis of Alzheimer's Disease
Open this publication in new window or tab >>Lysosomal Involvement in the Pathogenesis of Alzheimer's Disease
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Alzheimer’s disease (AD), the major cause of senile dementia, is associated with progressive formation of neurofibrillary tangles and extraneuronal plaques composed of amyloid beta peptide (Aβ). Aβ has been also found within Alzheimer neurons in association with the lysosomal system, an acidic vacuolar compartment possessing numerous hydrolytic enzymes. Lysosomes have been shown to be involved in both the formation of Aβ and its toxicity to neurons. Another line of evidence implicates oxidative stress as an important factor in the development of AD. It is reported that oxidative damage is one of the earliest changes in AD and plays an important role in the development of the disease. Although both the lysosomal system and reactive oxygen species are involved in AD, the mechanisms of this involvement are not well understood.

To gain insight into the relationship between oxidative stress and the lysosomal system in AD pathogenesis, we focused our study on: 1) The effect of oxidative stress on intracellular distribution of Aβ; 2) the role of endogenous Aβ in oxidant-induced apoptosis; 3) the role of autophagy and APP processing in oxidant induced damage; and, 4) the intraneuronal localization of Aβ and its relationship to the lysosomal system.

In our study, hyperoxia (40% versus 8% ambient oxygen) was used as a model of mild oxidative stress in vitro, while transfected cells producing different amounts of Aβ were used to assess toxicity due to endogenous Aβ. It was found that: 1) oxidative stress induces autophagic uptake of Aβ, resulting in its partial accumulation within lysosomes; 2) oxidative stress can induce neuronal death through macroautophagy of Aβ and consequent lysosomal membrane permeabilization; 3) increased cellular Aβ production is associated with enhanced oxidative stress and enhanced macroautophagy, resulting in increased intralysosomal Aβ accumulation and consequent apoptosis; and, 4) in normal conditions, intracellular Aβ shows primarily cytosolic distribution, not related to lysosomes and other acidic vacuoles, endoplasmic reticulum, Golgi complexes, synaptic vesicles or mitochondria. Only a minor portion of Aβ shows partial colocalization with cellular organelles. Inhibition of secretion significantly increased Aβ colocalization with endoplasmic reticulum, Golgi complexes, synaptic vesicles and lysosomes, as well as the amount of mitochondrial and cytosolic Aβ.

Oxidative stress induces intralysosomal autophagy-generated Aβ accumulation, consequently causing lysosomal membrane permeabilization and apoptosis. Our findings provide a possible explanation of the interactive role of oxidative stress and lysosomal system in AD pathogenesis, and may be helpful for a future therapeutic strategy against AD.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2012. 55 p.
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1282
National Category
Medical and Health Sciences
urn:nbn:se:liu:diva-73412 (URN)978-91-7393-005-5 (ISBN)
Public defence
2012-02-03, Berzeliussalen, ingång 65, Campus US, Linköpings universitet, Linköping, 13:00 (English)
Available from: 2012-01-03 Created: 2012-01-03 Last updated: 2012-01-05Bibliographically approved

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