Aging-induced immunological signature of the brain's choroid plexus negatively regulates neurogenesis and cognitive function

Reactive oxygen species (ROS) are major contributors to neuropathology in both Multiple sclerosis and other neurodegenerative disorders. ROS are small molecules with unpaired electrons, making them highly reactive and their actions need to be tightly regulated. ROS can initiate oxidative degradation of poly unsaturated lipids in the cell membrane leading to lipid peroxidation. In this process other reactive compounds are generated, among which 4-hydroxynonenal (4-HNE) is one. 4-HNE is in itself neurotoxic and has been associated with neurodegenerative diseases and occurs in MS lesions. The most efficient defense against free 4-HNE is Glutathione-S-transferase 4 alpha (Gsta4), which ligates HNE to glutathione. We have studied the influence of allelic variation in Gsta4 in combination with its transgenic modified expression in two models of inflammation/neurodegeneration; controlled contusion traumatic brain injury (TBI) and experimental autoimmune encephalomyelitis (EAE). Susceptibility was compared between Dark Agouti (DA), a congenic rat strain on DA backgroundwith a small chromosome 8 fragment containing an expression quantitative trait locus for Gsta4 and a Gsta4 transgenic strain on DA background. We find that high Gsta4 mRNA and protein levels correlate with increased nerve cell survival in the TBI model as well as after intrathecal 4-HNE administration. Allelic variation in Gsta4 does not statistically significantly affect the EAE score over 50 days, although there is a trend of improvedEAE score in the higherGsta4 expressing congenic strain. At the moment these findings are being repeated in the Gsta4 transgenic strain. Our data stresses Gsta4 as a key player in acute and chronic nerve cell degenerating conditions.