Oxidative stress and alterations in the mammalian iron metabolism : A study on iron, inflammation, oxidative stress and neurodegeneration

Sammanfattning: Iron is essential for all living organisms, from bacteria to man for a broad variety of biological functions, including oxygen transport and DNA synthesis. However, iron can also be toxic, due to its involvement in the formation of highly reactive oxygen species through Fenton chemistry. Iron has been suggested to be involved in the pathology of several neurodegenerative disorders, including Alzheimer’s and Parkinson’s disease as well as prion diseases, such as Creutzfeldt-Jakob’s disease and scrapie. The work presented in this thesis is linked to the intracellular iron metabolism, oxidative stress and inflammation.Studies of iron metabolism in scrapie infected neuroblastoma N2a cells indicate that the scrapie infection is lowering the levels of both total iron and the labile iron pool. We also detected variations in the activities of iron regulatory protein 1 and 2 in the scrapie infected cells as compared to control cells. In addition, we have used DNA microarrays to compare the expression levels of mRNAs corresponding to several genes important for the antioxidative defense such as glutathione peroxidase and glutathione transferases between scrapie infected N2a and control cells. Our results suggest that the scrapie infected cells show differences in the expression of important genes involved in the cellular defense against oxidative stress as compared to control cells.We have also studied alterations in the iron metabolism as a response to the bacterial toxin lipopolysaccharide (LPS). LPS treatment leads to a decrease of transferrin receptor protein (TfR) and to an increase of ferritin mRNA levels in N2a and BV-2 cells. The decrease of TfR expression is dependent on reactive oxygen species (ROS) and nitric oxide (NO) species, whereas the increase of ferritin mRNA is independent of both ROS and NO formation.Finally, we have studied the effect of sulfide on iron regulation in RD4 cells. We detected a substantial sulfide-induced increase in the labile iron pool. We also measured markedly elevated levels of ferritin protein and a decrease in IRP2 protein, indicating that the released iron was made bioavailable.