The finding that oxidative damage, including that to nucleic acids, in Alzheimer's disease is primarily limited to the cytoplasm of susceptible neuronal populations suggests that mitochondrial abnormalities might be part of the spectrum of chronic oxidative stress of Alzheimer's disease. In this study, we usedin situhybridization to mitochondrial DNA (mtDNA), immunocytochemistry of cytochrome oxidase, and morphometry of electron micrographs of biopsy specimens to determine whether there are mitochondrial abnormalities in Alzheimer's disease and their relationship to oxidative damage marked by 8-hydroxyguanosine and nitrotyrosine. We found that the same neurons showing increased oxidative damage in Alzheimer's disease have a striking and significant increase in mtDNA and cytochrome oxidase. Surprisingly, much of the mtDNA and cytochrome oxidase is found in the neuronal cytoplasm and in the case of mtDNA, the vacuoles associated with lipofuscin. Morphometric analysis showed that mitochondria are significantly reduced in Alzheimer's disease. The relationship shown here between the site and extent of mitochondrial abnormalities and oxidative damage suggests an intimate and early association between these features in Alzheimer's disease.

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Publication costs assisted by Brookhaven National Laboratory Single-photon ionization quantum yields are reported for tetramethyl-p-phenylenediamine (TMPD) as a function of wavelength and temperature in various dielectric liquids. At 23°the maximum quantum yield is observed at short wavelengths and is 0.07 in tetramethylsilane, less in cyclopentane, 2,2,4-trimethylpentane, and 2,2-dimethylbutane, and ~10~B in n-alkanes (C4-C14). In the n-alkanes there is a marked temperature effect on the quantum yield. For branched hydrocarbons the effect of temperature is less pronounced. The variation in yields with temperature is accounted for by the Onsager equation; this suggests that (ion pairs) is close to unity and that electrons and cations separate characteristic distances in each liquid. These distances range from 31 Á in n-hexane to 106 Á in tetramethylsilane. Wavelengths for ionization onsets depend on the energy of the excess electron (Vo) in the solvent and are used to evaluate this quantity for 18 different liquids. The results also suggest that V0 shifts toward more positive values at lower temperatures.

There is a great deal of evidence that places oxidative stress as a proximal event in the natural history of Alzheimer disease (AD). In addition to increased damage, there are compensatory increases in the levels of free sulfhydryls, glucose-6-phosphate dehydrogenase, and NAD(P)H:quinone oxidoreductase 1. To investigate redox homeostasis further in AD, we analyzed protein disulfide isomerase (PDI), a multifunctional enzyme, which catalyzes the disruption and formation of disulfide bonds. PDI plays a pivotal role in both secreted and cell-surface-associated protein disulfide rearrangement. In this study, we show that PDI specifically localizes to neurons, where there is no substantial increase in AD compared to age-matched controls. These findings indicate that the neurons at risk of death in AD do not show a substantial change in PDI to compensate for the increased sulfhydryls and reductive state found during the disease. This suggests that, despite compensatory reductive changes in AD, the level of PDI is sufficiently high physiologically in neurons to accommodate a more reducing environment.

Crushed unripe walnut hulls (Juglans nigra), when extracted with ether, yield an extract which sedates or at least depresses the movements of Daphnia magna, leopard frogs, perch, catfish, goldfish, mice, rats, and rabbits. One purified depressant compound, 5-hydroxy-1,4-naphthoquinone (juglone), has been isolated and tested on most of these species.