Thiamine (vitamin B1) deficiency (TD) produces a mild, chronic impairment of oxidative metabolism that models the diminished metabolism and reduced activities of the thiamine-dependent mitochondrial enzymes that occur in brain in several common age-related neurodegenerative disorders. Regionally selective neurodegeneration and activation of astrocytes, microglia and endothelial cells occur in TD and in these diseases. Vascular changes, inflammatory responses, oxidative stress and neuronal death are present in brains from TD mice and in brains from patients who die from common neurodegenerative diseases. A mechanistic sequence of events cannot be discovered in autopsied human brain, but can be studied effectively in experimental animals. Several features of the TD model make it amenable to analysis of the interactions leading to neurodegeneration: 1) The time course of the events leading to neuronal death is prolonged (11 days). 2) The death occurs in a discrete nucleus with a well-defined number of neurons. 3) The model exists in mice so transgenic animals can be used to test mechanism. The proposed experiments will test the following hypothesis: TD-induced abnormafities in metabolism increase neural production of cytokines, which activate microglia and astrocytes and stimulate endothelial cells to promote entry of peripheral immune cells. Cytotoxic compounds that are released from these activated cells combine to produce neurodegeneration. The underlying mechanisms will be tested in vivo by the strategy successfully used in our ongoing experiments. The sequences of responses of cell-specific changes in markers of inflammation, vascular responses and oxidative stress will be established. Specific drug treatments and, where feasible, transgenic animals will be used to test whether each specific step is critical in the cascade leading to neurodegeneration. An understanding of these mechanisms will likely suggest new ways to overcome the consequences of the mild, chronic impairment of oxidative metabolism that accompanies numerous age-related neurodegenerative disorders.
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