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Alzheimer's disease

Fig. 2. The consequences of an altered SOD1 to GPx1 ratio in Down syndrome (DS). An imbalance in the SOD1 to GPx1 ratio results in the build-up of reactive oxygen species (ROS). ROS have been implicated in numerous pathologies that also occur as part of the DS phenotype, such as premature aging, neurological disorders and Alzheimer's disease (AD). An understanding of how ROS contribute to individual pathologies aids in the understanding of more complex situations such as DS. In particular, ROS have been implicated in the formation of Ap, the neurotoxic protein found in AD plaques, via a mechanism that includes the redox-sensitive transcription factor ETS-2 and the P-amyloid precursor protein (APP). This process, in turn, generates more ROS, thereby further fueling the build-up of A|P Increased ROS also affects inflammatory pathways via activation of the redox-sensitive transcription factor NF-kB, which in turn increases expression of the interleukins, IL-1, IL-6 and tumor necrosis factor, TNF-a. This in turn generates more ROS, thereby enhancing inflammatory processes.

CONCLUSIONS/DISCUSSION AND FUTURE DIRECTIONS FOR THERAPEUTIC INTERVENTIONS

This chapter has focused on the consequences of an altered antioxidant ratio (SOD1:GPx1) in order to assess its contribution to the DS phenotype. It has highlighted that all DS fetal organs investigated to date display an altered SOD1 to GPx1 ratio, and it showed the many manifestations of an altered ratio both in in vitro and in vivo contexts. In particular, data from our laboratory and others have highlighted the role that an altered antioxidant ratio and oxidative stress play in cellular senescence, neurodegeneration and A toxicity, all pathophysiological conditions known to occur prematurely in DS. An understanding of the genes located on HSA21 and their contribution to the various pathologies associated with DS, may assist in the design of therapeutics aimed at alleviating some of these pathologies.

The DS genotype is determined at conception, but therapeutics able to assist those with DS will greatly reduce the pathological burden and its negative impact on the quality of life of these individuals. Supplementation with antioxidants to reduce the level of oxidative stress might offer some protective advantages to individuals with DS. Alpha-tocopherol (vitamin E), a lipid-soluble vitamin that interacts with cell membranes trapping free radicals, has been shown to reduce the degeneration of hippocampal cells after cerebral ischemia (109) and cell death associated with ^-amyloid protein (110). In a randomized controlled trial of vitamin E supplementation to individuals with AD, vitamin E was found to delay functional deterioration in these patients and was suggested as a beneficial treatment (111). Since individuals with DS almost invariably develop AD-like deposits in their brains, treatment of DS patients with vitamin E might lessen or prevent A$ deposition (111).

Vitamins such as C, ^-carotene and selenium (the co-factor required for GPx function) may have important antioxidant functions and have been suggested as beneficial in individuals with DS (112). One study worthy of note is that by Antila et al. (113), who administered selenium to seven DS patients for 0.3-1.5 years and reported a 25% increase in GPx activity and a 24% reduction in the SOD1 to GPxl ratio. Supplementation of selenite clearly benefited these DS patients through optimization of their antioxidant protection by GPx. However, to date other antioxidant trials have been largely equivocal in their outcomes and have targeted older DS individuals for whom the antioxidant regime may have had limited value. Indeed our data (32) and that of others (114) suggest that ROS-mediated damage begins in utero and that interventions to limit damage should begin soon after birth.

Finally, it should be emphasized that studies at the molecular level add a further dimension for future therapeutics in DS. Our data has highlighted the consequences of an altered antioxidant ratio in DS and suggests that trying to correct the antioxidant balance may be beneficial in vulnerable organs such as the brain. It is only by clearly defining the molecular basis of pathologies like DS that one can hope to design drugs to reduce or ameliorate these detrimental gene-dosage effects.

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