Normal Glutamate Metabolism in Alzheimer's Disease Fibroblasts Deficient in α-Ketoglutarate Dehydrogenase Complex Activity

Cooper, Arthur J. L.; Sheu, Kwan‐Fu Rex; Blass, John P.

doi:10.1159/000111446

Cited by 14 publications

(7 citation statements)

References 9 publications

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“…This last result has been confirmed in an independent series of experiments showing inherent defect of the a-ketoglutarate dehydrogenase complex (83). Glutamine oxidation also declines (59,79,80) in AD cells, although not always (84). Furthermore, reduced cytochrome c oxidase (CO) activity was demonstrated in platelets derived from AD patients (85) and also in AD fibroblasts from our bank (Govoni et al, unpublished results).…”

Section: Alterations In Oxidative Metabolism In Ad Peripheral Cellssupporting

confidence: 79%

Peripheral markers in testing pathophysiological hypotheses and diagnosing Alzheimer's disease

Gasparini¹,

Racchi²,

Binetti³

et al. 1998

FASEB j.

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Alterations in amyloid precursor protein (APP) metabolism, calcium regulation, oxidative metabolism, and transduction systems have been implicated in Alzheimer's disease (AD). Limitations to the use of postmortem brain for examining molecular mechanisms underscore the need to develop a human tissue model representative of the pathophysiological processes that characterize AD. The use of peripheral tissues, particularly of cultured skin fibroblasts derived from AD patients, could complement studies of autopsy samples and provide a useful tool with which to investigate such dynamic processes as signal transduction systems, ionic homeostasis, oxidative metabolism, and APP processing. Peripheral cells as well as body fluids (i.e., plasma and CSF) could also provide peripheral biological markers for the diagnosis of AD. The criteria required for a definite diagnosis of AD presently include clinical criteria in association with histopathologic evidence obtained from biopsy or autopsy. Thus, the use of peripheral markers as a diagnostic tool, either to predict or at least to confirm a diagnosis, may be of great importance. Gasparini, L., Racchi, M., Binetti, G., Trabucchi, M., Solerte, S. B., Alkon, D., Etcheberrigaray, R., Gibson, G., Blass, J., Paoletti, R., Govoni, S. Peripheral markers in testing pathophysiological hypotheses and diagnosing Alzheimer's disease. FASEB J. 12, 17–34 (1998)

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Section: Alterations In Oxidative Metabolism In Ad Peripheral Cellssupporting

confidence: 79%

Peripheral markers in testing pathophysiological hypotheses and diagnosing Alzheimer's disease

Gasparini¹,

Racchi²,

Binetti³

et al. 1998

FASEB j.

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“…66 In intact AD fibroblasts, oxidation of [ 14 C]glutamate to 14 CO 2 is reduced, 67,68 but the contents of glutamate and related amino acids appear normal. 69 These results are consistent with KGDHC being less "rate limiting" (i.e., having a lower control coefficient) in cultured fibroblasts than in brain.…”

Section: Abnormalities In Energy/oxidative Metabolism In Nonneural Adsupporting

confidence: 78%

Inherent Abnormalities in Energy Metabolism in Alzheimer Disease: Interaction with Cerebrovascular Compromise

Blass

Sheu

Gibson

2000

Annals of the New York Academy of Sciences

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170

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Alzheimer disease (AD) is a form of the dementia syndrome. AD appears to have a variety of fundamental etiologies that lead to the neuropathological manifestations which define the disease. Patients who are at high risk to develop AD typically show impairments of cerebral metabolic rate in vivo even before they show any evidence of the clinical disease on neuropsychological, electrophysiological, and neuroimaging examinations. Therefore, impairment in energy metabolism in AD can not be attributed to loss of brain substance or to electrophysiological abnormalities. Among the characteristic abnormalities in the AD brain are deficiencies in several enzyme complexes which participate in the mitochondrial oxidation of substrates to yield energy. There include the pyruvate dehydrogenase complex (PDHC), the alpha-ketoglutarate dehydrogenase complex (KGDHC), and Complex IV of the electron transport chain (COX). The deficiency of KGDHC may be due to a mixture of causes including damage by free radicals and perhaps to genetic variation in the DLST gene encoding the core protein of this complex. Inherent impairment of glucose oxidation by the AD brain may reasonably be expected to interact synergistically with an impaired supply of oxygen and glucose to the AD brain, in causing brain damage. These considerations lead to the hypothesis that cerebrovascular compromise and inherent abnormalities in the brain's ability to oxidize substrates can interact to favor the development of AD, in individuals who are genetically predisposed to develop neuritic plaques.

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“…Its relatively low activity in brain compared with activities of other mitochondrial constituents suggests that even a subtle impairment of KGDHC could affect mitochondrial oxidation in brain (Blass, 1993;Cooper et a!., 1996). The early reduction of KGDHC activity in both affected and unaffected areas (a 30-40% reduction by day 11; Table 1 and Fig.…”

Section: Pathologic Significance Of Kgdhc Deficiency In Tdmentioning

confidence: 99%

Immunochemical Characterization of the Deficiency of the α‐Ketoglutarate Dehydrogenase Complex in Thiamine‐Deficient Rat Brain

Sheu

Calingasan

Lindsay

et al. 1998

Journal of Neurochemistry

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Abstract:Mitochondrial dysfunction is a common feature of many neurodegenerative disorders. The metabolic encephalopathy caused by thiamine deficiency (TD) is a classic example in which an impairment of cerebral oxidative metabolism leads to selective cell death. In experimental TD in rodents, a reduction in the activity of the thiamine diphosphate-dependent, mitochondrial enzyme a-ketoglutarate dehydrogenase complex (KGDHC) occurs before the onset of pathologic lesions and is among the earliest biochemical deficits found. To understand the molecular basis and the significance of the deficiency of KGDHC in TD-induced brain damage, the enzyme activity and protein levels of KGDHC were analyzed. The effect of TD on the subregional/cellular distribution of KGDHC and the anatomic relation of KGDHC with selective cell death were also tested by immunocytochemistry. Consistent with several previous studies, TD dramatically reduced KGDHC activity in both anatomically damaged (thalamus and inferior colliculus) and spared (cerebral cortex) regions. Immunocytochemistry revealed no apparent correlation of regional KGDHC immunoreactivity or its response to TD with affected regions in TD. The basis of the enzymatic and immunocytochemical behavior of KGDHC was further assessed by quantitative immunoblots, using antibodies specific for each of the three KGDHC components. Despite the marked decrease of KGDHC activity in TD, no reduction of any of the three KGDHC protein levels was found. Thus, TD impairs the efficacy of the KGDHC catalytic machinery, whereas the concentration of protein molecules persists. The generalized decline of KGDHC activity with no apparent anatomic selectivity is consistent with the notion that the compromised mitochondrial oxidation sensitizes the brain cells to various other insults that precipitate the cell death. The current TD model provides a relevant experimental system to understand the molecular basis of many neurodegenerative conditions in which mitochondrial dysfunction and KGDHC deficiency are prominent features. Key Words: Alzheimer's disease-et-Ketoglutarate dehydrogenase-2-Oxoglutarate dehydrogenaseOxidative stress-Thiamine deficiency-Thiamine diphosphate-dependent enzymes-Wernicke-Korsakoff's syndrome.

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Normal Glutamate Metabolism in Alzheimer's Disease Fibroblasts Deficient in α-Ketoglutarate Dehydrogenase Complex Activity

Cited by 14 publications

References 9 publications

Peripheral markers in testing pathophysiological hypotheses and diagnosing Alzheimer's disease

Peripheral markers in testing pathophysiological hypotheses and diagnosing Alzheimer's disease

Inherent Abnormalities in Energy Metabolism in Alzheimer Disease: Interaction with Cerebrovascular Compromise

Immunochemical Characterization of the Deficiency of the α‐Ketoglutarate Dehydrogenase Complex in Thiamine‐Deficient Rat Brain

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