Cytochrome oxidase in Alzheimer's disease: Biochemical, histochemical, and immunohistochemical analyses of the visual and other systems

Wong‐Riley, Margaret T.T.; Antuono, Piero; Ho, K C; Egan, Robert A.; Hevner, Robert F.; Liebl, Wendy; Huang, Zifang; Rachel, Rivka A.; Jones, Jim R.

doi:10.1016/s0042-6989(96)00210-6

Cited by 116 publications

(62 citation statements)

References 60 publications

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“…These mitochondrial components are likely damaged, because hydroxynonenal adducts to lipoic acid (Humphries and Szweda, 1998), the prosthetic group of two key Krebs cycle enzymes, can be found in the same vacuoles substantiates the view that these components are nonfunctional (G. Perry, M. A. Smith, and L. Szweda, unpublished observations). Also, because cytochrome oxidase must be membrane-bound to function, our findings are consistent with the low functional activity of many mitochondrial enzymes in AD (Wong-Riley et al, 1997).…”

Section: Discussionsupporting

confidence: 84%

“…Dysfunction of mitochondrial electron transport proteins has been associated with the pathophysiology of AD (Blass and Gibson, 1991), as well as in Parkinson's disease (Parker et al, 1989). Those studies that analyzed mitochondrial function at the cellular level, through cytochrome oxidase activity measurements, have consistently shown activity deficits consistent with mitochondrial compromise (Wong-Riley et al, 1997). Furthermore, cytoplasmic hybrid cells in which mitochondria from sporadic cases of AD were fused with other cells also indicate a defect in mitochondria function in AD (Ghosh et al, 1999;Khan et al, 2000;Trimmer et al, 2000).…”

Section: Abstract: Alzheimer's Disease; Free Radicals; Metabolism; Mmentioning

confidence: 99%

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Mitochondrial Abnormalities in Alzheimer's Disease

Aliev²,

et al. 2001

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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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Section: Discussionsupporting

confidence: 84%

Section: Abstract: Alzheimer's Disease; Free Radicals; Metabolism; Mmentioning

confidence: 99%

Mitochondrial Abnormalities in Alzheimer's Disease

Aliev²,

et al. 2001

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“…Increased MtDNA damage and reduced MtDNA content in AD were associated with reduced expression of mitochondrial protein and COX, and reduced MitoTracker Green labeling. Although reduced COX expression in AD has been reported previously (Chandrasekaran et al, 1998;Nagy et al, 1999;Wong-Riley et al, 1997), the present study provides new information indicating that in AD, impaired mitochondrial function with reduced expression of mitochondriaencoded genes is likely caused by MtDNA damage. In addition, enhanced MtDNA damage results in reduced mitochondrial mass (mitochondrial protein expression, MitoTracker Green labeling) and reduced MtDNA content.…”

Section: Discussionsupporting

confidence: 51%

Mitochondrial DNA Damage as a Mechanism of Cell Loss in Alzheimer's Disease

Monte

Luong

Neely

et al. 2000

Laboratory Investigation

205

125

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SUMMARY:Aging is associated with impaired mitochondrial function caused by accumulation of oxygen free radical-induced mitochondrial (Mt) DNA mutations. One prevailing theory is that age-associated diseases, including Alzheimer's disease (AD), may be precipitated, propagated, or caused by impaired mitochondrial function. To investigate the role of MtDNA relative to genomic (Gn) DNA damage in AD, temporal lobe samples from postmortem AD (n ϭ 37) and control (n ϭ 25) brains were analyzed for MtDNA and GnDNA fragmentation, mitochondrial protein and cytochrome oxidase expression, MitoTracker Green fluorescence (to assess mitochondrial mass/abundance), and 8-oxo-7,8-dihydro-2Ј-deoxyguanosine (8-OHdG) immunoreactivity. Brains with AD had more extensive nicking and fragmentation of both MtDNA and GnDNA as demonstrated by agarose gel electrophoresis, end-labeling, and the in situ terminal deoxynucleotide transferase end-labeling (TUNEL) assay, and only the brains with AD had detectable 8-OHdG immunoreactivity in cortical neurons. Increased MtDNA damage in AD was associated with reduced MtDNA content, as demonstrated by semiquantitative PCR analysis and reduced levels of Mt protein and cytochrome oxidase expression by Western blot analysis or immunohistochemical staining with image analysis. The finding of reduced MitoTracker Green fluorescence in AD brains provided additional evidence that reduced Mt mass/abundance occurs with AD neurodegeneration. The presence of increased MtDNA and GnDNA damage in AD suggest dual cell death cascades in AD. Impaired mitochondrial function caused by MtDNA damage may render brain cells in AD more susceptible to oxidative injury and thereby provide a mechanism by which systemic or environmental factors could influence the course of disease. (Lab Invest 2000, 80:1323-1335.

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“…A similar finding was made in AD brains in 1992 (Parker et al, 1990a;Kish et al, 1992). Subsequently, the finding of reduced COX activity in AD patients has been replicated in platelets Bosetti et al, 2002;Cardoso et al, 2004a), fibroblasts (Curti et al, 1997), focal brain regions (Bosetti et al, 2002), and large parts of the brain (Mutisya et al, 1994;Wong-Riley et al, 1997). These reports indicate mitochondrial dysfunction occurs in AD and that AD mitochondrial dysfunction is systemic rather than brain-limited.…”

Section: Alzheimer's Diseasesupporting

confidence: 58%

Mitochondria in Neurodegeneration

Swerdlow

2011

Neural Metabolism in Vivo

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Many neurodegenerative diseases demonstrate abnormal mitochondrial morphology and biochemical dysfunction. Alterations are often systemic rather than brain-limited. Mitochondrial dysfunction may arise as a consequence of abnormal mitochondrial DNA, mutated nuclear proteins that interact directly or indirectly with mitochondria, or through unknown causes. In most cases it is unclear where mitochondria sit in relation to the overall disease cascades that ultimately causes neuronal dysfunction and death, and there is still controversy regarding the question of whether mitochondrial dysfunction is a necessary step in neurodegeneration. In this chapter we highlight and catalogue mitochondrial perturbations in some of the major neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD). We consider data that suggest mitochondria may be critically involved in neurodegenerative disease neurodegeneration cascades. Keywordscybrid; mitochondria; mitochondrial DNA; neurodegenerative disease The quintessential neurodegenerative diseasesNeurodegenerative diseases are characterized by gradually progressive, selective loss of anatomically or physiologically related neuronal systems. The clinical syndromes associated with particular neuroanatomical patterns of cell dysfunction and loss are typically categorized by whether they initially affect cognition, movement, strength, coordination, sensation, vision, or autonomic control. Prototypical examples include AD, PD, ALS, and HD. HD is strictly an autosomal dominant disorder. With AD, PD, and ALS most cases are age-related and show sporadic epidemiology, although rare Mendelian variants do occur. As life expectancy continues to advance in developed countries the incidence of these disorders increases and will continue to do so.Mitochondrial dysfunction is a common theme in these diseases. Mitochondria are known to play a central role in many cell functions including ATP generation, intracellular Ca 2+ homeostasis, reactive oxygen species (ROS) formation, and apoptosis. Neurons are particularly dependent on mitochondria because of their high energy demands. It seems reasonable to hypothesize neurons are relatively intolerant of mitochondrial dysfunction. This assumption is supported by the fact that maternally inherited diseases with known homoplasmic or near-homoplasmic mitochondrial DNA (mtDNA) mutations tend to affect the central nervous system and muscle, the body's two most aerobic tissues.

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Cytochrome oxidase in Alzheimer's disease: Biochemical, histochemical, and immunohistochemical analyses of the visual and other systems

Cited by 116 publications

References 60 publications

Mitochondrial Abnormalities in Alzheimer's Disease

Mitochondrial Abnormalities in Alzheimer's Disease

Mitochondrial DNA Damage as a Mechanism of Cell Loss in Alzheimer's Disease

Mitochondria in Neurodegeneration

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