1972 BUTTERFIELD latter radicals, in turn, react with other lipid-resident allylic hydrogen atoms to form lipid hydroperoxides and additional carbon-centered lipid radicals, propagating the chain reaction. Lipid hydroperoxides can undergo decomposition to HNE, acrolein, isoprostanes, and other molecules. Reactive alkenals (HNE; acrolein) react with protein-resident cysteine, histidine, and lysine residues by Michael addition (4, 8) to form covalent adducts that affect the structure (25) and function (13) of modified brain proteins. Oxidative stress also leads to loss of the reducing environment of cells, primarily loss of glutathione (GSH) and thioredoxin (TRX) levels to form the respective oxidative products. Changes in redox environment of cells lead to cellular stress responses, some of which are restorative (21) and some of which are detrimental to the cell (18). For example, a decreased ratio of GSH to GSSG triggers liberation of the transcription factor Nrf2 from Keap1, permitting translocation of Nrf2 from the cytoplasm to the nucleus, where it binds to the antioxidant response element (ARE) of DNA (6, 15). This, in turn, leads to increased production of antioxidant-related enzymes, including those necessary to increase GSH production. In contrast, changes in the redox status of neurons can trigger death signals, resulting in apoptotic processes and death of neurons (18).

The level of protein oxidation in cells is a consequence of the interplay of the formation and removal of such oxidatively modified proteins. For example, enzymes such as methionine sulfoxide reductase, carbonyl reductase, and aldehyde reductase convert oxidatively modified proteins back to their native states (4, 11). Moreover, degradation of oxidatively modified or aggregated proteins is mostly accomplished via action of the complex machinery of the proteasome (10). As elegantly discussed in this issue by Halliwell, when the proteasome itself is compromised, neurodegeneration can occur, in part because of the effects of oxidative stress (10).