Degeneration of neurons and associated reactions of non-neuronal cells are cardinal neuropathological features of neurodegenerative disorders in humans. Yet neither the spatiotemporal relationship of neuronal degeneration to non-neuronal cell reactions nor the mechanisms which elicit such non-neuronal cell reactions, are well understood. Glial cell reactions to neuronal injury have been studied experimentally in axotomy or toxicant-lesioned models. As far as we know, however, there are no studies on the glial cell reactions associated with spontaneous neuronal degeneration caused by metabolic perturbation. We recently observed microglial activation in well defined regions corresponding to the site of neuronal degeneration in the brain of hemizygous brindled mottled mouse, which is similar to human Menkes' kinky hair disease, We hypothesize that degenerating neurons release some factor(s) which stimulate regional glial cell proliferation and attract migration of glial cells from the adjacent area by chemotaxis. Using this model, several aims are planned; 10 to study the spatiotemporal relationship between degeneration of neurons and activation of non-neuronal cells, in particular of microglial cells; 20 to identify and characterize the cells which express the major histocompatibility complex antigens in the regions of neuronal degeneration; and 3) to explore the possible mechanisms of such cellular reactions. In addition, we also plan to investigate the possible age related differences in responses of non-neuronal cells to neuronal injury. The animal model to be used for most studies is a murine mutant brindled mottled, in which degeneration of neurons develops in well-defined regions of the cerebral cortex and thalamus. The techniques to be used are light and electron microscopy, immunocytochemistry, autoradiography, fluorescent microscopy, computer assisted 3-d reconstruction, cell isolation and tissue culture.
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