Oxidative stress induces macroautophagy of amyloid beta-protein and ensuing apoptosis

Lin Zheng, Katarina Kågedal, Nodi Dehvari, Eirikur Benedikz, Richard Cowburn, Jan Marcusson, Alexei Terman

Research output: Contribution to journalJournal articleResearchpeer-review

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.

Original languageEnglish
JournalFree Radical Biology & Medicine
Volume46
Issue number3
Pages (from-to)422-9
Number of pages8
ISSN0891-5849
DOIs
Publication statusPublished - 1 Feb 2009
Externally publishedYes

Keywords

  • Alzheimer Disease
  • Amyloid beta-Peptides
  • Apoptosis
  • Autophagy
  • Cell Line, Tumor
  • Cell Membrane Permeability
  • Humans
  • Intracellular Membranes
  • Journal Article
  • Lysosomes
  • Mutant Proteins
  • Neurons
  • Oxidative Stress
  • Oxygen
  • Research Support, Non-U.S. Gov't
  • Transfection
  • Transgenes

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