COBRE: UND: TNF-ALPHA/GLUTAMATE INDUCED CELL DEATH IN ALZHEIMER'S DISEASE

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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 plaques in AD brains, their precise contribution to cell loss remains speculative. In vitro, fibrils stimulate microglia to secrete neurotoxic products suggesting that microglial inflammation directly contributes to cell death in AD. Preliminary evidence demonstrates that amyloid beta fibrils stimulate cultured mouse microglia to secrete the excitatory neurotransmitter, glutamate, and the pro-inflammatory cytokine, TNF alpha. 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 receptor (p55) and NMDA receptors, as neither factor, alone, is sufficient to initiate cell death. Accordingly, we will test the hypothesis that AD brains provide the appropriate microglial-mediated inflammatory environment for TNF alpha and glutamate to synergistically stimulate TNF alpha and glutamate receptor signaling pathways and cause 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 TNF alpha and the glutamate receptor agonist, NMDA. 2) Identify the mechanisms of nontoxic TNF alpha alone and nontoxic NMDA alone-mediated signaling responses in neurons. 3) Determine the mechanisms of the synergistic TNF alpha + NMDA mediated signaling cross-talk responsible for oxidative damage-dependent neuron death.