Peroxynitrite Mediates Neurotoxicity of Amyloid β-Peptide 1-42- and Lipopolysaccharide-Activated Microglia

Zhong Xie, Min Wei, Todd E. Morgan, Paola Fabrizio, Derick Han, Caleb E. Finch, Valter D. Longo*

*Corresponding author for this work

Research output: Contribution to journalArticle

233 Scopus citations

Abstract

The amyloid β-peptide (Aβ) activates microglia and promotes the generation of cytokines and oxygen species, including nitric oxide (NO) and tumor necrosis factor α (TNF-α), which can be either neurotoxic or neuroprotective. We show that neuron death in cocultures of rat cortical microglia and neurons activated by lipopolysaccharide (LPS) or Aβ 1-42 plus interferon γ (IFN-γ) is caused by short-lived diffusible molecules and follows the generation of superoxide and/or peroxynitrite as determined by electron paramagnetic spectroscopy. Neurotoxicity induced by LPS or Aβ1-42 plus IFNγ is blocked by inhibitors of NO synthesis and by the peroxynitrite (ONOO -) decomposition catalysts FeTMPyP [5,10,15,20-tetrakis(n-methyl-4′-pyridyl) porphinato iron (III) chloride] and FeTPPS [5,10,15,20-tetrakis(4-sulfonatophenyl)prophyrinato iron (III) chloride] but not by the TNF-α inhibitor pentoxifylline. The specificity of FeTMPyP for ONOO - was confirmed by its ability to block the toxicity of a peroxynitrite donor but not of NO donors or of high levels of superoxide in a yeast mutant lacking superoxide dismutase 1. These results implicate peroxynitrite as a mediator of the toxicity of activated microglia, which may play a major role in Aβ1-42 neurotoxicity and Alzheimer's disease.

Original languageEnglish (US)
Pages (from-to)3484-3492
Number of pages9
JournalJournal of Neuroscience
Volume22
Issue number9
DOIs
StatePublished - May 1 2002

Keywords

  • LPS
  • Microglia
  • Neurons
  • Nitric oxide
  • Peroxynitrite
  • Superoxide
  • TNF-α

ASJC Scopus subject areas

  • Neuroscience(all)

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