Apolipoprotein E Oxidation and Functional Consequences

Many theories have been advanced to account for the ageing process. Among them, the free radical theory of ageing remains the most generally accepted (Emerit and Chance 1992). The brain is believed to be particularly vulnerable to oxidative damage, as it contains high concentrations of easily peroxidizable lipids (i.e., those rich in polyunsaturated fatty acids), has regions particularly enriched in iron, and has comparatively low to moderate levels of endogenous antioxidant molecules (Halliwell 1992; Harris 1992). The activity of antioxi dant enzymes like superoxide dismutase and catalase is increased in Alzheimer’s disease (AD) brain (Balazs and Leon 1994; Palmer and Burns 1994). Protein oxidation products are reportedly increased in both aged rodent and human brains (Fucci et al. 1983; Smith et al. 1991), as well as in Alzheimer’s patients (Volicer and Crino 1990). Measurements on postmortem brain samples have effectively shown that, compared with young controls, samples from aged groups have an increased carbonyl content and decreased glutamine synthetase and creatine kinase activities, two enzymes that are efficiently inhibited by radical oxygen species. These modifications are more marked in the frontal than in the occipital region. This suggests that, whereas protein oxidation products accumulate in the brain, oxidation-sensitive enzyme activities decrease with ageing in the same regional pattern (Smith et al. 1991). Overexpression of the cytochrome-oxidase gene has also been shown by Northern blot analysis in AD patients (Alberts et al. 1992).