Peroxynitrite Mediates Neurotoxicity of Amyloid β-Peptide 1–42 - and Lipopolysaccharide-Activated Microglia
Open accessAbstract
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.
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O2− and NO combine at diffusion-limited rates to form highly reactive ONOO− that has been implicated in the death of cultured neurons or oligodendrocyte progenitors exposed to LPS-activated microglia.
“O 2 ⅐Ϫ and NO⅐ combine at diffusion-limited rates to form highly reactive ONOO Ϫ that has been implicated in the death of cultured neurons or oligodendrocyte progenitors exposed to LPS-activated microglia (Xie et al., 2002;Li et al., 2005).”
From Neurotoxic Activation of Microglia Is Promoted by a Nox1-Dependent NADPH Oxidase (2008) · cites this paper as Xie et al., 2002
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- Authors
- Xie, Z., Wei, M., Morgan, T. E., Fabrizio, P., Han, D., Finch, C. E., & Longo, V. D.
- Affiliations
- Department of Biological Sciences (RU)
- University of Southern California (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2002-05-01
- Volume
- 22
- Issue
- 9
- Pages
- 3484-3492
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6758387
- OpenAlex
- W4297793640
- Cited by
- 272
- References
- 3
- Citations by year
- 2026: 1 · 2025: 6 · 2024: 2 · 2023: 4 · 2022: 9 · 2021: 4 · 2020: 4 · 2019: 7 · 2018: 5 · 2017: 10 · 2016: 2 · 2015: 9 · 2014: 16 · 2013: 7 · 2012: 11
- FWCI
- 13.64
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neuroscience (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- PubMed
- Funders
- John Douglas French Alzheimer's Foundation
- National Institutes of Health
- National Institute on Aging (K01AG001028, R01AG013499)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Keywords
- peroxynitrite, amyloid beta peptide 1-42, lipopolysaccharide, microglial activation, neurotoxicity, interferon-gamma, superoxide, nitric oxide, FeTMPyP, FeTPPS, Alzheimer's disease, neuroinflammation, cortical neurons, peroxynitrite decomposition
- MeSH terms
- Animals, Cell Separation, Cell Survival, Cells, Cultured, Dose-Response Relationship, Drug, Electron Spin Resonance Spectroscopy, Enzyme Inhibitors, Immunosuppressive Agents, Interferon-gamma, Lipopolysaccharides, Neurons, Pentoxifylline, Peptide Fragments, Rats, Inbred F344, Superoxides, Thalidomide, Tumor Necrosis Factor-alpha, Amyloid beta-Peptides, Microglia, Coculture Techniques, Nitric Oxide Synthase, Peroxynitrous Acid, Rats, Iron Compounds
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