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Tumor necrosis factor alpha: uncovering regulation mechanisms on ionotropic receptors in the CNS.

Excitotoxic activation of N-methyl-D-aspartate (NMDA) receptors is a mechanism of neuron death commonly hypothesized to occur in various neuroinflammatory paradigms including Alzheimer's disease. Although changes in glutamate release or uptake may precipitate this excessive receptor activity, it is possible that other factors also contribute to excitotoxic activation. For example, tumor necrosis factor alpha (TNF[alpha]) is a pleotropic cytokine that is elevated in the central nervous system in a diverse set of neuroinflammatory conditions where it may contribute to death or protection through binding to either TNFRI or TNFRII receptors. Previously, we demonstrated that TNF[alpha] stimulated neuronal NMDAR activity resulting in an ERK-dependent death mechanism mediated via TNFRII since agonist antibody for TNFRII but not TNFRI stimulated NMDA receptor-dependent [Ca.sup.2+] influx and death. We hypothesize that elevated concentrations of TNF[alpha] may potentiate neuron death even in the absence of excitotoxic glutamate levels. In order to further define the effect of TNF[alpha] on NMDAR-dependent action we stimulated primary mouse cortical neuron cultures at 14 days in vitro with TNF[alpha] and TNFRI/TNFRII agonist antibody. Agonist antibody for TNFRII but not TNFRI were toxic alone and potentiated NMDA receptor-dependent toxicity. This correlated with the ability of TNF[alpha] and TNFRII agonist antibodies to stimulate increased NMDA receptor activity as observed by increased intracellular [Ca.sup.2+] levels and NMDA receptor-evoked currents. In addition, using two different techniques to assess surface expression of receptors (biotinylation assays and immunocytochemistry with non-permeabilizing conditions); we observed an increase in the surface localization of NMDAR1 and GluR1 subunits after transient TNF[alpha] or TNFRII stimulation. Preliminary data suggests that the TNFRII-stimulated change in NR1 localization is mediated by PKC activity since the PKC inhibitor, Go36976, blocks this response. These data suggest a novel mechanism whereby elevated levels of proinflammatory cytokines, particularly TNF[alpha], may contribute to neuron loss during disease via potentiation of excitotoxicity.



J. H. JARA (1), B. B. SINGH (2), S. LEI (1), C. K. COMBS (1)

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Title Annotation:COMMUNICATIONS--UNDERGRADUATE; central nervous system
Author:Jara, J.H.; Singh, B.B.; Lei, S.; Combs, C.K.
Publication:Proceedings of the North Dakota Academy of Science
Article Type:Report
Geographic Code:1USA
Date:Apr 1, 2008
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