The amyloid 13 protein induces oxidative damage of mitochondrial DNA

Peter Bozner, Valentina Grishko, Susan P. LeDoux, Glenn L. Wilson, Y. C. Chyan, Miguel A. Pappolla

Research output: Contribution to journalReview article

93 Scopus citations

Abstract

Multiple lines of evidence suggest involvement of oxidative stress in the pathogenesis of Alzheimer disease (AD). The finding that amyloid beta peptide (Aβ) has neurotoxic properties and that such effects are mediated in part by free-radicals has provided an avenue to explore new therapeutic strategies. In this study, we showed that exposure of PC12 cells to an Aβ fragment induces oxidative damage of mitochondrial DNA. Cells were exposed for 24 h to 50 μM Aβ (25-35) or to 50 μM of a control peptide with a scrambled sequence. Oxidative damage of mitochondrial DNA (mtDNA) was assessed using a Southern blot technique and an mtDNA-specific probe recognizing a 13.5-kilobase restriction fragment. Treatment of DNA with NaOH was used to reveal abasic sites and single strand breaks. Treatment with endonuclease III or FAPy glycosylase was used to detect pyrimidine or purine lesions, respectively. Cells exposed to Aβ exhibited marked oxidative damage of mtDNA as evidenced by characteristic changes on Southern blots. Cells exposed to the scrambled peptide did not show such modifications. Simultaneous addition of the pineal hormone melatonin consistently prevented the Aβ-induced oxidative damage to mtDNA. Mitochondrial dysfunction in AD has been demonstrated by several laboratories. This study provides experimental evidence supporting a causative role of Aβ in mitochondrial lesions of AD.

Original languageEnglish (US)
Pages (from-to)1356-1362
Number of pages7
JournalJournal of Neuropathology and Experimental Neurology
Volume56
Issue number12
DOIs
StatePublished - Dec 1997

Keywords

  • Alzheimer disease
  • Amyloid
  • Beta peptide
  • DNA
  • Melatonin
  • Mitochondria
  • Oxidative stress

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Neurology
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

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