Microglial-dependent inflammation is critical for neurodegenerative conditions ranging from Alzheimer's disease (AD) to multiple sclerosis and Parkinson's disease. Therefore toxic microglial proinflammatory products as well as their specific mechanisms of neuronal toxicity are likely common to numerous pathological situations. Identifying the nature of these toxins as well as their modes of action will provide molecular targets for preventing the inflammatory changes in numerous neurodegenerative conditions. Although abundant reactive microglia are found associated with beta-amyloid (AB) plaques in AD brains, their precise contribution to cell loss remains speculative. In vitro, AB fibrils stimulate microglia to secrete neurotoxic products suggesting that microglial inflammation directly contributes to cell death in AD. Preliminary evidence demonstrates that A]3 fibrils stimulate cultured mouse microglia to secrete the excitatory neurotransmitter, glutamate, and the pro-inflammatory cytokine, TNFa. These proinflammatory secretions directly induce death of mouse cortical neuron cultures in an oxidative damage-dependent fashion requiring increased neuronal expression of inducible nitric oxide synthase and subsequent peroxynitrite production. Neuron death results from coincident stimulation of the TNF-RI and NMDA receptors, as neither factor, alone, is sufficient to initiate cell death. These findings, suggest the hypothesis that AD brains provide the appropriate microglial-mediated inflammatory environment for TNFa and glutamate to synergistically stimulate toxic, chronic activation of TNFa and glutamate receptor signaling pathways in neurons as a contributing mechanism of cell death. The following specific aims will address this hypothesis: 1) Determine whether necrotic or apoptotic cell death is induced by synergistic stimulation of neuronal cortical cultures with TNFa and the glutamate NMDA receptor agonist, NWIDA. 2) Identify the mechanisms of nontoxic TNFa alone and nontoxic NMDA alone-mediated signaling responses in neurons. 3) Determine the mechanism of the synergistic TNFa +NMDA mediated signaling cross-talk responsible for oxidative damage-dependent neuron death.
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