Deficiency of Tnf Receptors Suppresses Microglial Activation and Alters the Susceptibility of Brain Regions to Mptp-induced Neurotoxicity: Role of Tnf-alpha.
From: Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, Morgantown, West Virginia 26505, USA.
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
- Publish Date: Apr 2006
- ISSN: 1530-6860
- Volume: 20
- Issue: 6
- Pages: 670-82
- Medium: Internet
- Language: English
- Citation (JAMA): Sriram Krishnan, Matheson Joanna M, Benkovic Stanley A, et al. Deficiency of Tnf Receptors Suppresses Microglial Activation and Alters the Susceptibility of Brain Regions to Mptp-induced Neurotoxicity: Role of Tnf-alpha.. FASEB J. Apr 2006;20:670-82
Abstract
Enhanced expression of tumor necrosis factor (TNF) -alpha, is associated with the neuropathological effects underlying disease-, trauma- and chemically induced neurodegeneration. Previously, we have shown that deficiency of TNF receptors protects against MPTP-induced striatal dopaminergic neurotoxicity, findings suggestive of a role for TNF-alpha in neurodegeneration. Here, we demonstrate that deficiency of TNF receptors suppresses microglial activation and alters the susceptibility of brain regions to MPTP. MPTP-induced expression of microglia-derived factors, TNF-alpha, MCP-1, and IL-1alpha, preceded the degeneration of striatal dopaminergic nerve terminals and astrogliosis, as assessed by loss of striatal dopamine and TH, and an increase in striatal GFAP. Pharmacological neuroprotection with the dopamine reuptake inhibitor, nomifensine, abolished striatal dopaminergic neurotoxicity and associated microglial activation. Similarly, in mice lacking TNF receptors, microglial activation was suppressed, findings consistent with a role for TNF-alpha in striatal MPTP neurotoxicity. In the hippocampus, however, TNF receptor-deficient mice showed exacerbated neuronal damage after MPTP, as evidenced by Fluoro Jade-B staining (to identify degenerating neurons) and decreased microtubule-associated protein-2 (MAP-2) immunoreactivity. These effects were not accompanied by microglial activation, but were associated with increased oxidative stress (nitrosylation of tyrosine residues). These findings suggest that TNF-alpha exerts a neurotrophic/neuroprotective effect in hippocampus. The marked differences we observed in the regional density, distribution and/or activity of microglia and microglia-derived factors may influence the region-specific role for this cell type. Taken together, our results are indicative of a region-specific and dual role for TNF-alpha in the brain: a promoter of neurodegeneration in striatum and a protector against neurodegeneration in hippocampus.
Mesh Headings (Keywords): 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine, Animals, Brain, Corpus Striatum, Cytokines, Dopamine, Gene Expression Regulation, Hippocampus, MPTP Poisoning, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Microglia, NF-kappa B, Nomifensine, Oxidative Stress, Receptors, Tumor Necrosis Factor, Tumor Necrosis Factor-alpha
Check for Full Text / PubMed Unique Identifier (PMID): 16581975
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