Oxidative metabolism in cultured fibroblasts derived from sporadic Alzheimer's disease (AD) patients

Curti, Daniela; Rognoni, F; Gasparini, Laura; Cattaneo, Achille; Paolillo, Mayra; Racchi, Marco; Zani, L.; Bianchetti, Angelo; Trabucchi, Marco; Bergamaschi, S.; Govoni, Stefano

doi:10.1016/s0304-3940(97)00741-6

Cited by 76 publications

(47 citation statements)

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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: 59%

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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Section: Alzheimer's Diseasesupporting

confidence: 59%

Mitochondria in Neurodegeneration

Swerdlow

2011

Neural Metabolism in Vivo

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“…This notion is supported by an extensive literature which reports that AD is characterized by reduced cerebral energy metabolism (8), impaired activities of the tricarboxylic acid cycle enzymes (25,121,162), and defects in the mitochondrial ETC (21,32,45,146,96,193). The most consistent defect at ETC level is the decline in cytochrome c oxidase (COX) activity, an effect that is positively correlated with Ab concentration, as determined by in vitro studies (30).…”

Section: Oxidative Stress In the Aging Brainmentioning

confidence: 83%

Mitochondrial DNA Oxidative Damage and Repair in Aging and Alzheimer's Disease

Santos

Correia

Zhu

et al. 2013

Antioxidants & Redox Signaling

146

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“…First, a catalytic abnormality in CO has been found in AD brains (Parker et al, 1994b) as well as peripheral AD tissues where it is much less likely to have resulted from secondary neuronal downregulation or another nonspecific cause. This primary CO impairment in AD cells cannot be attributable to nonspecific neuron atrophy or loss because it has been found in non-neural cells, such as platelets (Parker et al, 1990(Parker et al, , 1994a, fibroblasts (Curti et al, 1997), and skeletal muscle (Gonzalez-Lima et al, 1998b). A CO decrement in these various peripheral tissues indicates that a CO impairment may exist in addition to any local neuropathology or neuronal atrophy in the AD brain.…”

Section: Discussionmentioning

confidence: 97%

Energy Hypometabolism in Posterior Cingulate Cortex of Alzheimer's Patients: Superficial Laminar Cytochrome Oxidase Associated with Disease Duration

2001

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Among brain regions affected in Alzheimer's disease (AD), the posterior cingulate shows the earliest and largest decrement in energy metabolism. Positron emission tomography (PET) studies have shown that these decrements appear before the onset of memory deficits or other symptoms in persons at genetic risk for AD. This study compares in vivo imaging results and in situ postmortem analyses by examining the posterior cingulate (area 23) in 15 AD patients and 13 age-matched nondemented controls using quantitative cytochrome oxidase histochemistry as an intracellular measure of oxidative energy metabolic capacity. Each of the six layers of the posterior cingulate demonstrated a decline in cytochrome oxidase activity in AD relative to controls, whereas adjacent motor cortex showed no significant differences. This decrement did not appear to be mainly secondary to nonspecific decrement in mitochondrial enzymes, oxidative stress, cell loss, or histopathology. The cytochrome oxidase decrement was most severe in the superficial layer I (Ϫ39%), which demonstrated a correlation to disease duration. Covariance analyses suggest that superficial laminas undergo a functional uncoupling from the deeper layers of posterior cingulate cortex in AD, whereas no such effects are found in motor cortex or controls. These findings expand on previous results from PET studies by illuminating the layer-specific cytochrome oxidase contributions to energy hypometabolism. The findings suggest a decrement of cytochrome oxidase in posterior cingulate cortex, with progressive reduction within the superficial laminas linked to disease duration. Such decrement could contribute to some of the behavioral symptoms displayed by AD patients. This decrement appeared greater in women.Key words: cytochrome oxidase; energy metabolism; posterior cingulate cortex; Alzheimer's disease; brain mapping; gender Decrements in energy metabolism are one of the earliest detectable abnormalities in Alzheimer's disease (AD). Positron emission tomography (PET) studies on subjects homozygotic for the ⑀4 allele of the apolipoprotein E (APOE) gene, with no symptoms of AD, demonstrate metabolic reductions in posterior cingulate, parietal, temporal, and prefrontal cortices (Reiman et al., 1996;Small et al., 2000). Their largest decrement was in the posterior cingulate cortex (PCC) (Reiman et al., 1996), as in the case of AD (Minoshima et al., 1994). Another PET study (Minoshima et al., 1997) confirmed that although normal subjects show intense PCC metabolic activity, early-stage AD patients suffered a PCC decrement (21-22%) that was significantly greater than that seen in other cortical regions. This greater hypometabolism determined by PET is not merely an artifact of generalized atrophy (Ibanez et al., 1998) or AD histopathology that is lower in PCC than the other regions (Braak and Braak, 1998), although degeneration of PCC occurs in AD (Brun and Gustafson, 1976). Severity of AD symptoms is correlated with hypoactivity in PCC but not temporal regions, as measured with PE...

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Oxidative metabolism in cultured fibroblasts derived from sporadic Alzheimer's disease (AD) patients

Cited by 76 publications

References 20 publications

Mitochondria in Neurodegeneration

Mitochondria in Neurodegeneration

Mitochondrial DNA Oxidative Damage and Repair in Aging and Alzheimer's Disease

Energy Hypometabolism in Posterior Cingulate Cortex of Alzheimer's Patients: Superficial Laminar Cytochrome Oxidase Associated with Disease Duration

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