Despite remarkable progress in the areas of molecular genetics and the cell biology of amyloid precursor protein, the proximate causes of the neuronal degeneration in Alzheimer's disease (AD) remain unknown. A pathogenetic mechanism that has been established as responsible for neuron death in other age-related neurodegenerative conditions is oxidative stress. It is now established that one cause of amyotrophic lateral sclerosis (ALS) is a defect in antioxidant defenses due to missense mutations in the gene encoding Cu/Zn superoxide dismutase. How this defect leads to the selective vulnerability of certain motor neuron populations, which is a hall-mark of ALS, is unknown. Here, we propose to assess the idea that genes coding for molecules related to antioxidant defenses are differentially expressed in ALS-vulnerable versus ALS-resistant motor pools. We will then test the hypothesis that increasing antioxidant defenses will prevent motor neuron death in the proximal axotomy model of motor neuron degeneration in adult animals. Lines of transgenic mice over- expressing bcl-2, a proto-oncogene which blocks apoptotic cell death and is linked to antioxidant defenses, will be used in these experiments. A source of oxidative stress, hypothesized to be important in sporadic ALS, is excessive activation of glutamate receptors. However, whether excessive activation of glutamate receptors can actually cause chronic motor neuron death in vivo is unknown. In preliminary experiments we have shown that brief treatment with the NMDA-receptor antagonist MK-801 markedly enhances motor neuron death after distal axotomy in adult animals. We now plan to test the hypothesis that this motor neuron death is associated with upregulation of gene expression for NMDA receptor subunits. In addition we will ask whether upregulation of non-NMDA receptors may cause motor neuron death in the same paradigm by combining axotomy with brief treatment with the non-NMDA blocker, NBQX. These experiments will characterize differences in antioxidant defenses between ALS-resistant and vulnerable motor neuron populations and test the hypothesis that increasing antioxidant defenses can save motor neurons in adult models of neuronal degeneration. Furthermore, this work will assess the importance of glutamate receptor regulation to long-term motor neuron survival in vivo. The results should provide insights into the phenomenon of selective neuronal vulnerability, a prominent feature of all age- related neurodegenerative conditions including AD.
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