Peroxynitrite mediates neurotoxicity of amyloid beta-peptide1-42- and lipopolysaccharide-activated microglia.
The amyloid beta-peptide (Abeta) activates microglia and promotes the generation of cytokines and oxygen species, including nitric oxide (NO) and tumor necrosis factor alpha (TNF-alpha), 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 Abeta1-42 plus interferon gamma (IFNgamma) 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 Abeta1-42 plus IFNgamma 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-alpha 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 Abeta1-42 neurotoxicity and Alzheimer's disease.
Xie
Zhong
Z
Division of Biogerontology, Andrus Gerontology Center, and Department of Biological Sciences, University of Southern California, Los Angeles, California 90089-0191, USA.
Wei
Min
M
Morgan
Todd E
TE
Fabrizio
Paola
P
Han
Derick
D
Finch
Caleb E
CE
Longo
Valter D
VD
D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D002469:Cell Separation; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D018920:Coculture Techniques; D004305:Dose-Response Relationship, Drug; D004578:Electron Spin Resonance Spectroscopy; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology; D058085:Iron Compounds / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D017628:Microglia / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D010431:Pentoxifylline / Q000494:pharmacology; D010446:Peptide Fragments / Q000633:toxicity*; D030421:Peroxynitrous Acid / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344; D013481:Superoxides / Q000378:metabolism; D013792:Thalidomide / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors
D016229:Amyloid beta-Peptides; D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D058085:Iron Compounds; D008070:Lipopolysaccharides; D010446:Peptide Fragments; D014409:Tumor Necrosis Factor-alpha; C075222:amyloid beta-protein (1-42); D013481:Superoxides; D030421:Peroxynitrous Acid; D013792:Thalidomide; D007371:Interferon-gamma; D019001:Nitric Oxide Synthase; D010431:Pentoxifylline