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Thiamine deficiency (TD) models the selective neurodegeneration that accompanies the mild impairment of oxidative metabolism, which is observed in a variety of neurodegenerative diseases. Several markers of inflammation accompany neuronal death in TD and in these diseases. Studies in the submedial thalamic nucleus (SmTN), the region most sensitive to TD, have begun to define the temporal response of inflammation, immune response and neurodegeneration. Our previous studies show that the immune response is involved in TD-induced neurodegeneration. The current experiments tested the roles of other inflammatory cascades in TD-induced neuronal death. Deletion of genes for CD4, or CD8 (the co-receptors for T-cells), IFN-gamma (the cytokine produced by T-cell), or NADPH oxidase (the inflammation related oxidase) were tested. None protected against neuronal death in late stages of TD. On the other hand, deletion of the genes for CD4, CD8 and IFN-gamma increased the microglial activation, and deletion of the gene for NADPH oxidase decreased microglial activation when compared to control mice. In wild type mice, TD caused hypertrophy of CD68 positive microglia without increasing the number of microglia. However, TD induced hypertrophy and proliferation of CD68-positive microglia in the CD4 (97%), CD8 (57%) or IFN-gamma (96%) genetic knockout mice. In the genetic knockout mice for NADPH oxidase, the microglial activation was 65% less than the wild type mice. The results demonstrate that mice deficient in specific T cells (CD4-/-, CD8-/-) or activated T cell product, (IFN-gamma-/-) have increased microglia activation, but mice deficient in NADPH oxidase have decreased microglial activation. However, at the time point tested, the deletions were not neuroprotective. The results suggest that inflammatory responses play a role in TD-induced pathological changes in the brain, and the inflammation appears to be a late event that reflects a response to neuronal damage, which may spread the damage to other brain regions.

Abnormalities in oxidative processes, region-selective neuron loss, inflammation and diminished activity of thiamine-dependent enzymes characterize age-related neurodegenerative diseases. Thiamine deficiency (TD) models the selective neurodegeneration that accompanies mild impairment of oxidative metabolism. As in human neurodegenerative diseases, alterations in multiple cell types accompany the TD-induced neurodegeneration. The current studies demonstrate that CD40 and CD40 ligand (CD40L), two co-stimulatory immune molecules, are involved in TD-induced selective neuronal death. TD induced CD40 immunoreactivity in microglia and CD40L immunoreactivity in astrocytes. Both CD40-positive microglia and CD40L-positive astrocytes increased during the progressive TD-induced neuronal death. In early stages of TD, targeted deletion of CD40 diminished the number of CD40L-positive astrocytes and reduced neuronal death by 35%. The number of CD40L-positive astrocytes increased whenever the number of NeuN-positive neurons decreased. In early stages of TD, deletion of CD40L diminished CD40-positive microglia and reduced the neuronal death by 64%. In advanced phases of TD, neither CD40 nor CD40L deletion protected against neuronal death. The data show for the first time that TD induces expression of CD40 by the microglia and CD40L by astrocytes. The results indicate that CD40-CD40L interactions promote neuronal death in early stages of TD, but that at later phases the protective effects of the diminished CD40 or CD40L are over-ridden by other mechanisms.

Thiamine (Vitamin B1) deficiency (TD) leads to memory deficits and neurological disease in animals and humans. The thiamine-dependent enzymes of the tricarboxylic acid (TCA) cycle are reduced following TD and in the brains of patients that died from multiple neurodegenerative diseases. Whether reductions in thiamine or thiamine-dependent enzymes leads to changes in all TCA cycle enzymes has never been tested. In the current studies, the pyruvate dehydrogenase complex (PDHC) and all of enzymes of the TCA cycle were measured in the brains of TD mice. Non-thiamine-dependent enzymes such as succinate dehydrogenase (SDH), succinate thiokinase (STH) and malate dehydrogenase (MDH) were altered as much or more than thiamine-dependent enzymes such as the alpha-ketoglutarate dehydrogenase complex (KGDHC) (-21.5%) and PDHC (-10.5%). Succinate dehydrogenase (SDH) activity decreased by 27% and succinate thiokinase (STH) decreased by 24%. The reductions in these other enzymes may result from oxidative stress because of TD or because these other enzymes of the TCA cycle are part of a metabolon that respond as a group of enzymes. The results suggest that other TCA cycle enzymes should be measured in brains from patients that died from neurological disease in which thiamine-dependent enzymes are known to be reduced. The diminished activities of multiple TCA cycle enzymes may be important in our understanding of how metabolic lesions alter brain function in neurodegenerative disorders.

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.