Interspecies differences in glial secretions contributing to neuronal survival and death

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The neurodegenerative disorders of humans (e.g. Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis) and animals (e.g. scrapie, bovine spongiform encephalopathy) are characterised by irreversible loss of neurons. The non-neuronal cells in the brain, including microglia and astrocytes, can affect neuronal survival significantly. They do so by secreting various mediators that either enhance neuronal survival (i.e. neurotrophic factors) or cause neuronal death (i.e. neurotoxins). Furthermore, when these cells become activated, the repertoire of neuroactive molecules that they secrete may depend not only on the type of stimulus they encounter but also on the species of origin of the cells. Thus far, no systematic study has explored this aspect of glia-neuron signaling. Furthermore, there are glial mediators that have not been described yet. The proposed research will address these issues by studying secretions of microglial cells and astrocytes from humans and several other mammals, including rats, mice, pigs and sheep. I will analyse neuroactive products that are released by these cells after their exposure to several stimulants that are relevant to both human and animal neurodegenerative pathology and inflammatory mechanisms. I will also investigate the secretory arsenal of several glia-like cell lines to assess their usefulness as models of primary glial cells and I will search for novel, yet unidentified, neuroactive products of glial cells by using an unbiased proteomics technique. The proposed research program will answer a fundamental biological question about whether there are essential differences between glial cells from different species in their secretory responses to specific stimuli. An important practical application, crucial to an effective drug discovery process and translational research for human and animal neurodegenerative diseases, will be identification of the most appropriate in vitro model systems and species suitable for such research. These model systems could be used by other researchers to develop drugs with beneficial action in various neurodegenerative disorders of humans and animals, which could have substantial economic as well as health benefits to Canada.