ABSTRACT
Specialized DHA-enriched membranes of axons and synaptosomes as well as polyunsaturated membranes of neuron mitochondria are major substrates or targets for chemical oxidation. It is now clear that neurons have evolved numerous robust mechanisms for protecting their membranes against lipid peroxidation (see Chapter 10). Antioxidants are one of the most important lines of defense against membrane defects caused by oxidation. According to conventional theories of membrane peroxidation, DHA and polyunsaturated fatty acid chains in neuron membranes are €rst attacked by reactive oxygen species generating more reactive oxygen species in a snowballing chemical reaction (see Chapter 14). Chemists classify this as a chain reaction that, if uncontrolled, can destroy cellular function. Antioxidants, including ascorbic acid, emphasized here along with vitamin E, work together in neurons by snuf€ng out free radicals that feed a chain reaction. Reactive oxygen species are generated as a natural by-product of electron transport in neuron mitochondria, by lipid peroxidation of polyunsaturated membranes and during oxidative bursts of microglia as disease-€ghting cells in the brain. It is not possible to completely stop production of reactive oxygen species in neurons, and it is not possible to develop a perfect shield against the toxic effects of these free radicals. These data gave rise to the popular oxidative stress theory of aging in which reactive oxygen species escaping cellular defenses directly attack mitochondrial DNA (mtDNA), creating mutations followed by energy stress that causes aging. According to this model, oxidatively derived mutations in mtDNA are envisioned to be the primary cause of energy de€cits driving the process of aging.
