Cytochrome Oxidase Inhibition: A Novel Animal Model of Alzheimer's Disease

Mc, Bennett; Dm, Diamond; Sl, Stryker; Jk, Parks; Wd, Parker

doi:10.1177/002383099200500206

Cited by 69 publications

(26 citation statements)

References 45 publications

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“…In addition to deficiencies in COX, deficiencies in pyruvate dehydrogenase complex (PDHC), and the a-ketoglutarate dehydrogenase complex (KGDHC) have also been reported in AD [14][15][16]. COX is complex IV of the mitochondrial respiratory electron transport chain enzyme, which interacts directly with molecular oxygen.…”

Section: Discussionmentioning

confidence: 99%

Amyloid-β-Peptide Reduces the Expression Level of Mitochondrial Cytochrome Oxidase Subunits

et al. 2007

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Mitochondrial dysfunction is an important cause of neurological disorder including Alzheimer's disease (AD). Mitochondria play a key role in the generation of reactive oxygen species (ROS), resulting in oxidative damage to neuronal cell and cellular compartments in the AD brain. Cytotoxicity induced by amyloid-beta (Abeta), a protein fragment of 25-35 amino acids in amyloid plaques has been shown to have neuro-toxic properties. They seem to involve mitochondrial dysfunction, but the underlying mechanisms are not clearly understood. The purpose of this study was to assess whether Abeta induced mitochondrial dysfunction involves changes in cytochrome c oxidase (COX) expression. We measured the activities of COX after expose of SK-N-SH cells (a human neuroblastoma cell line) to Abeta. We found that levels of mRNAs expressing mitochondrial COX subunits decreased significantly in Abeta-treated SK-N-SH cells in a dose-dependent manner. Human mitochondrial transcription factor-1 (TFAM) mRNA level also decreased after Abeta-treatment. These results suggest that Abeta modulates the mitochondrial gene expression through a decrease in TFAM.

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Section: Discussionmentioning

confidence: 99%

Amyloid-β-Peptide Reduces the Expression Level of Mitochondrial Cytochrome Oxidase Subunits

et al. 2007

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“…As well, activities of CO have been found to be reduced in postmortem brain tissue homogenates from AD patients (Kish et al, 1992), and in the dentate gyrus and hippocampus using histochemistry (Simonian and Hyman, 1993). Perhaps one of the most relevant studies in implicating the involvement of CO in Alzheimer's is that of Bennett et al (1992) in which it was demonstrated that treatment of rats with sodium azide, a selective inhibitor of CO, served as a model for some of the characteristics of AD. This represents a milestone in that it is not yet known whether the histopathological changes found in AD, specifically the build up of amyloid Additionally, it has been demonstrated that 3-nitropropionic acid (3-NPA), an inhibitor of succinate dehydrogenase (complex II), can model the striatal neurodegeneration found in Huntington's disease, an effect which can be reversed by the implantation of genetically altered fibroblasts which secrete high levels of Nerve Growth Factor (NGF) (Frim et al, 1993).…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial enzyme deficiencies in Down's syndrome

Prince

Jia

Båve

et al. 1994

J Neural Transm Gen Sect

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Defects in cytochrome oxidase (CO; complex 4) have recently been demonstrated in blood platelets and in brain tissue from patients with Alzheimer's disease (AD) with possible etiological implications. Because of pathogenetic similarities with AD, we have measured the activities of several mitochondrially localised enzymes in the blood platelets of individuals afflicted with trisomy-21 (Down's syndrome). The activities of monoamine oxidase, cytochrome oxidase, isocitrate dehydrogenase, and glutamate dehydrogenase were assayed in washed platelets from sixty caucasian, male and female control individuals (ages 18-60) and ten, young Down's Syndrome patients (ages 9-21). Significant reductions in the activities of monoamine oxidase, cytochrome oxidase, and isocitrate dehydrogenase were found. In all cases the average activities in Down's syndrome individuals were approximately two-thirds those of controls (DS/Controls = 0.68, 0.67, 0.64 respectively). The activity of the fourth enzyme studied, glutamate dehydrogenase, was found to be similar to controls. Results suggest that these reductions are a consequence of a generalised mitochondrial disturbance which may lie behind some pathogenetic aspect(s) of the disease.

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“…Previously, NaN 3 (5-10 mM) was used to inhibit oxidative energy production in cultured astrocytes 14,29,30 and systemically in animals. [31][32][33][34][35] Other recent studies using cell culture and tissue-based assays have also relied on NaN 3 to generate chemical hypoxia. 36,37 In addition to cytochrome oxidase, NaN 3 also inhibits nucleoside triphosphate diphosphohydrolase, an ecto-diphosphohydralase that hydrolyzes nucleosides extracellularly at pH 8.…”

Section: Metabolic Inhibitorsmentioning

confidence: 99%

Glycolytic glioma cells with active glycogen synthase are sensitive to PTEN and inhibitors of PI3K and gluconeogenesis

Beckner

Gobbel

Abounader

et al. 2005

Laboratory Investigation

104

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Increased glycolysis is characteristic of malignancy. Previously, with a mitochondrial inhibitor, we demonstrated that glycolytic ATP production was sufficient to support migration of melanoma cells. Recently, we found that glycolytic enzymes were abundant and some were increased in pseudopodia formed by U87 glioma (astrocytoma) cells. In this study, we examined cell migration, adhesion (a step in migration), and Matrigel invasion of U87 and LN229 glioma cells when their mitochondria were inhibited with sodium azide or limited by 1% O 2 . Cell migration, adhesion, and invasion were comparable, with and without mitochondrial inhibition. Upon discovering that glycolysis alone can support glioma cell migration, unique features of glucose metabolism in astrocytic cells were investigated. The ability of astrocytic cells to remove lactate, the inhibitor of glycolysis, via gluconeogenesis and incorporation into glycogen led to consideration of supportive genetic mutations. Loss of phosphatase and tensin homolog (PTEN) releases glycogenesis from constitutive inhibition by glycogen synthase kinase-3 (GSK3). We hypothesize that glycolysis in gliomas can support invasive migration, especially when aided by loss of PTEN's regulation on the phosphatidylinositol-3 kinase (PI3K)/Akt pathway leading to inhibition of GSK3. Migration of PTEN-mutated U87 cells was studied for release of extracellular lactic acid and support by gluconeogenesis, loss of PTEN, and active PI3K. Lactic acid levels plateaued and phosphorylation changes confirmed activation of the PI3K/Akt pathway and glycogen synthase when cells relied only on glycolysis. Glycolytic U87 cell migration and phosphorylation of GSK3 were inhibited by PTEN transfection. Glycolytic migration was also suppressed by inhibiting PI3K and gluconeogenesis with wortmannin and metformin, respectively. These findings confirm that glycolytic glioma cells can migrate invasively and that the loss of PTEN is supportive, with activated glycogenic potential included among the relevant downstream effects.

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Cytochrome Oxidase Inhibition: A Novel Animal Model of Alzheimer's Disease

Cited by 69 publications

References 45 publications

Amyloid-β-Peptide Reduces the Expression Level of Mitochondrial Cytochrome Oxidase Subunits

Amyloid-β-Peptide Reduces the Expression Level of Mitochondrial Cytochrome Oxidase Subunits

Mitochondrial enzyme deficiencies in Down's syndrome

Glycolytic glioma cells with active glycogen synthase are sensitive to PTEN and inhibitors of PI3K and gluconeogenesis

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