Many neurodegenerative diseases share increased oxidative stress, increased NOX and increased TLR expression [40]. We have previously found in mice that neuroinflammatory responses that increase NOX expression and levels of reactive oxygen species such as superoxide are linked to neurodegeneration [26]. Alcohol-induced neurodegeneration is found in frontal cortex and hippocampus in rodent models [20] and humans [21]. We found increased morphological microglial activation, NADPH oxidase gp91phox and superoxide levels, as well as activated caspase-3 and Fluoro-Jade B markers of neurodegeneration in both cortex and hippocampal dentate gyrus. Ethanol-poly I:C treatment had significantly higher levels of NOX gp91phox mRNA, NOX gp91phox + IR protein, superoxide levels and cell death markers. NOX expression was co-localized with markers of neurons and microglia. However, caspase-3 + IR cells and Fluoro-Jade B markers of cell death were predominantly found in NeuN + IR neurons. We have found human postmortem alcoholic brain has increased neuronal expression of NOX gp91phox + IR [26]. These studies are consistent with microglial proinflammatory amplification causing neuronal induction of NOX, increasing oxidative stress that causes neuronal death and neurodegeneration.
