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Patients with Down syndrome (DS) and Alzheimer's disease (AD) share a number of characteristic neuropathologic lesions. Several lines of evidence suggest that mitochondria and the oxidative stress response are involved in the pathogenesis of both conditions. In the process of investigating the stress response in DS, we discovered a defective basal expression of a major mitochondrial heat shock protein, chaperonin 60 (Cpn60) in non-transformed dermal fibroblast cell lines from DS individuals. Such a defect was not present in control cells that had been cultured under identical physiological growth conditions. A quantitative analysis by Western blots showed a marked reduction of Cpn60 per equal amount of total protein in DS cells to an average of 35% of normal. Northern blot studies confirmed the defect and also showed a marked reduction of the mRNA signal for Cpn60 in all the DS cell lines. To gain further information, experiments were conducted to study the rate of de-novo synthesis of Cpn60 at normal and supraoptimal temperatures in DS and controls. Results showed no significant differences between the two study groups. HSP60 is important in mitochondrial function and defects in these organelles have been reported in DS and AD. Thus, the findings may have potential implications in the neuropathology of DS.

In the sea of information for and against the role of amyloid in AD many of us have felt at times in akin circumstances. The hypothesis by Andorn and Kalaria that amyloid peptides could function both as antioxidants and pro-oxidants yet adds a new dimension of complexity to an already intricate problem in Alzheimer’s disease. These authors present evidence suggesting that various Aβ fragments can, under certain experimental conditions, behave as antioxidants by inhibiting ascorbate-induced lipid peroxidation of membrane fragment preparations obtained from postmortem human prefrontal and parietal cortex. These findings raise new and interesting issues regarding amyloid deposits in AD. During the last few years several laboratories have presented compelling evidence indicating that brains with AD are subject to a pervasive level of oxidative stress. One important set of data comes from in vitro models and suggests that the amyloid peptide, the main constituent of senile plaques, causes extensive degeneration and

A growing body of data suggests that free radicals are involved in the pathogenesis of Alzheimer's disease (AD). Increased expression of antioxidant enzymes, such as superoxide dismutase (SOD), and their co-localization to senile plaques and dystrophic neurites have established a firm association between free-radical mediated injury and the disease neuropathology. While several studies have confirmed these findings, there is conflicting information regarding the activity of some of the enzymes. In the current report, we assayed the activity of superoxide dismutase (SOD), catalase and glutathione peroxidase (GSH-Px) from the same areas of the tissue showing increased expression of SOD1 and SOD2 (parallel sequential slices). Nine brains with neuropathologically confirmed AD and six neuropathologically normal, age-matched, controls were examined. Despite marked increased expression of SOD1 and SOD2 within senile plaques in all the cases studied, the activities of SOD, GSH-Px and catalase were significantly lower in AD than in control brains. The difference was most profound in the case of catalase followed by GSH-Px and SOD. These data are in qualitative agreement with that of several laboratories, and support a decrease rather than an increase, in antioxidant enzyme activity. The findings suggest two main possibilities. On one hand, the observed reduced activity along with antigenically increased expression may be consistent with inactivation of excess protein that has been synthesized under conditions of high oxidative stress. Increased protein oxidation coupled with enzyme inactivation is a documented, aging-associated phenomenon. Alternatively, the increased immuno-reactivity may reflect a redistribution phenomenon as the enzymes become more concentrated at the sites of increased oxidative stress, despite an over all reduction in their activity.