Selective response of various brain cell types during neurodegeneration induced by mild impairment of oxidative metabolism.

Age-related neurodegenerative diseases are characterized by selective neuron loss, glial activation, inflammation and abnormalities in oxidative metabolism. Thiamine deficiency (TD) is a model of neurodegeneration induced by impairment of oxidative metabolism. TD produces a time-dependent, selective neuronal death in specific brain regions, while other cell types are either activated or unaffected. TD-induced neurodegeneration occurs first in a small, well-defined brain region, the submedial thalamic nucleus (SmTN). This discrete localization permits careful analysis of the relationship between neuronal loss and the response of other cell types. The temporal analysis of the changes in the region in combination with the use of transgenic mice permits testing of proposed mechanisms of how the interaction of neurons with other cell types produces neurodegeneration. Loss of neurons and elevation in markers of neurodegeneration are accompanied by changes in microglia including increased redox active iron, the induction of nitric oxide synthase (NOS) and hemeoxygenase-1, a marker of oxidative stress. Endothelial cells also show changes in early stages of TD including induction of intracellular adhesion molecule-1 (ICAM-1) and endothelial NOS. The number of degranulating mast cells also increases in early stages of TD. Alterations in astrocytes and neutrophils occur at later stages of TD. Studies with transgenic knockouts indicate that the endothelial cell changes are particularly important. We hypothesize that TD-induced abnormalities in oxidative metabolism promote release of neuronal inflammatory signals that activate microglia, astrocytes and endothelial cells. Although at early stages the responses of non-neuronal cells may be neuroprotective, at late phases they lead to entry of peripheral inflammatory cells into the brain and promote neurodegeneration.