title: Oxidative stress induces macroautophagy of amyloid beta-protein and ensuing apoptosis.
abstract: There is increasing evidence for the toxicity of intracellular amyloid beta-protein (Abeta) to neurons and the involvement of lysosomes in this process in Alzheimer disease (AD). We have recently shown that oxidative stress, a recognized determinant of AD, enhances macroautophagy and leads to intralysosomal accumulation of Abeta in cultured neuroblastoma cells. We hypothesized that oxidative stress promotes AD by stimulating macroautophagy of Abeta that further may induce cell death by destabilizing lysosomal membranes. To investigate such possibility, we compared the effects of hyperoxia (40% ambient oxygen) in cultured HEK293 cells that were transfected with an empty vector (Vector), wild-type APP (APPwt), or Swedish mutant APP (APPswe). Exposure to hyperoxia for 5 days increased the number of cells with Abeta-containing lysosomes, as well as the number of apoptotic cells, compared to normoxic conditions. The rate of apoptosis in all three cell lines demonstrated dependence on intralysosomal Abeta content (Vector<APPwt<APPswe). Furthermore, the degree of apoptosis was positively correlated with lysosomal membrane permeabilization, whereas inhibitors of macroautophagy and lysosomal function decreased oxidant-induced apoptosis and diminished the differences in apoptotic response between different cell lines. These results suggest that oxidative stress can induce neuronal death through macroautophagy of Abeta and consequent lysosomal membrane permeabilization, which may help explain the mechanisms behind neuronal loss in AD.
authors.affiliation: Division of Geriatric Medicine, Linköping University, SE-581 85 Linköping, Sweden. lin.zheng@liu.se
authors.forename: Lin
authors.initials: L
authors.lastname: Zheng
authors.forename: Katarina
authors.initials: K
authors.lastname: Kågedal
authors.forename: Nodi
authors.initials: N
authors.lastname: Dehvari
authors.forename: Eirikur
authors.initials: E
authors.lastname: Benedikz
authors.forename: Richard
authors.initials: R
authors.lastname: Cowburn
authors.forename: Jan
authors.initials: J
authors.lastname: Marcusson
authors.forename: Alexei
authors.initials: A
authors.lastname: Terman
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis / Q000235:genetics; D001343:Autophagy / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability / Q000235:genetics; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism; D008247:Lysosomes / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress; D010100:Oxygen / Q000494:pharmacology; D014162:Transfection; D019076:Transgenes
chemical_list: D016229:Amyloid beta-Peptides; D050505:Mutant Proteins; D010100:Oxygen