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The Journal of Neuroscience, May 1, 2002, 22(9):3484-3492

Peroxynitrite Mediates Neurotoxicity of Amyloid -Peptide_1-42- and Lipopolysaccharide-Activated Microglia

Zhong Xie¹, Min Wei¹, Todd E. Morgan¹, Paola Fabrizio¹, Derick Han², Caleb E. Finch^{1, *}, and Valter D. Longo^{1, *}

¹ Division of Biogerontology, Andrus Gerontology Center, and Department of Biological Sciences, and ² Department of Molecular Pharmacology and Toxicology, School of Pharmacy, University of Southern California, Los Angeles, California 90089

The amyloid -peptide (A) activates microglia and promotes the generation of cytokines and oxygen species, including nitric oxide (NO) and tumor necrosis factor  (TNF-), 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 A_1-42 plus interferon  (IFN) 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 A_1-42 plus IFN 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- 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 A_1-42 neurotoxicity and Alzheimer's disease.

Key words: peroxynitrite; A; LPS; microglia; neurons; superoxide; nitric oxide; TNF-

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^* C.E.F. and V.D.L. contributed equally to this work.

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Copyright © 2002 Society for Neuroscience  0270-6474/02/2293484-09$05.00/0

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