Oxidative damage, involving all categories of biological macromolecules, is greatly increased in Alzheimer disease. However, while there are signs of systemic alterations in oxidative balance, the significant increase in damage is restricted to the cell bodies of susceptible neurons in the disease. This localization is consistent with an abnormality in the neuronal cytoplasm. Ultrastructural analysis of the site of nucleic acid oxidation shows the damage is restricted to the endoplasmic reticulum and free ribosomes, while morphometic analysis shows that mitochondria are largely unchanged in size and number. In contrast, mitochondrial markers, such as mitochondrial DNA or cytochrome oxidase, are increased several fold suggesting that increased oxidative damage may be as much a result of decreased turnover of damaged components as it is of increased production of oxidized macromolecules. The extent of abnormalities, as well as their chronic nature, suggest that a fundamental metabolic compromise is crucial to disease development.
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