Affected enzyme activities in Alzheimer's disease are sensitive to antemortem hypoxia

Terwel, Dick; Bothmer, J.; Wolf, E.; Meng, Fanping; Jolles, J.

doi:10.1016/s0022-510x(98)00240-8

Cited by 52 publications

(50 citation statements)

References 36 publications

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“…PDH, pyruvate dehydrogenase. (Terwel et al 1998). It is of note here that the pH optimum of the brain mitochondrial a-KGDH is very narrow, between 7.2 and 7.4, and at pH values below 7.2 or above 7.8 the activity of the enzyme markedly decreased (Lai & Cooper 1986).…”

Section: A-kgdh Is a Crucial Target Of Reactive Oxygen Species In Thementioning

confidence: 66%

Alpha-ketoglutarate dehydrogenase: a target and generator of oxidative stress

Tretter

Ádám-Vizi

2005

Phil. Trans. R. Soc. B

370

285

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Alpha-ketoglutarate dehydrogenase (a-KGDH) is a highly regulated enzyme, which could determine the metabolic flux through the Krebs cycle. It catalyses the conversion of a-ketoglutarate to succinylCoA and produces NADH directly providing electrons for the respiratory chain. a-KGDH is sensitive to reactive oxygen species (ROS) and inhibition of this enzyme could be critical in the metabolic deficiency induced by oxidative stress. Aconitase in the Krebs cycle is more vulnerable than a-KGDH to ROS but as long as a-KGDH is functional NADH generation in the Krebs cycle is maintained. NADH supply to the respiratory chain is limited only when a-KGDH is also inhibited by ROS. In addition being a key target, a-KGDH is able to generate ROS during its catalytic function, which is regulated by the NADH/NAD C ratio. The pathological relevance of these two features of a-KGDH is discussed in this review, particularly in relation to neurodegeneration, as an impaired function of this enzyme has been found to be characteristic for several neurodegenerative diseases.

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Section: A-kgdh Is a Crucial Target Of Reactive Oxygen Species In Thementioning

confidence: 66%

Alpha-ketoglutarate dehydrogenase: a target and generator of oxidative stress

Tretter

Ádám-Vizi

2005

Phil. Trans. R. Soc. B

370

285

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“…1993] perhaps as character istic as the deficient activity of choline acelyltransferase [Terwel et al, 1994], Recent observations suggest that a variation in the DLST gene coding for the E2k compo nent of KGDHC may be a genetic risk factor for the common, late-onset form of AD Sheu et al, 1996]. However, the genetic defect in some of the early-onset, familial AD cells which have been shown to be deficient in KGDHC is now known to involve not DLST but rather a nearby but unrelated gene, that for presenilin 1 [Sherrington et al, 1995].…”

Section: Discussionmentioning

confidence: 99%

“…The abnormality in KGDHC in AD can be identified both in AD brain [Gibson et al, 1988: Butterworth andBesnard, 1990;Mastrogiacomo et al. 1993;Terwel et al, 1994] and in AD fibroblasts [Sheu et al, 1994;Sorbi et al, unpubl. ], but these deficiencies may be expected to be much more metabolically signifi cant in highly oxidative brain tissue in which KGDHC appears to be the rate-limiting enzyme of the Krebs tri carboxylic acid cycle than in cultured skin fibroblasts which are not highly oxidative and in which KGDHC is not the rate-limiting enzyme of the Krebs cycle.…”

Section: Discussionmentioning

confidence: 99%

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

Cooper

Sheu²,

Blass³

1996

Dev Neurosci

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Deficient activity of the α-ketoglutarate dehydrogenase complex (KGDHC) has been documented in Alzheimer disease (AD) brain and fibroblasts. We examined glutamate metabolism in intact AD fibroblasts previously shown to have reduced KGDHC activity to determine whether this enzyme deficiency leads to a metabolic deficit in extraneural tissues. After exposure to [¹³N]ammonia for 5 min, the ratio of [¹³N]glutamate to [¹³N]aspartate and the ratio of unlabeled glutamate to aspartate were comparable in AD and control fibroblasts. The ratio of [¹³N]glutamate/[¹³N]glutamine was 3.7 ± 1.8 in AD and 6.8 ± 2.8 in control cells, but the difference was not statistically significant. Unlabeled glutamate/glutamine ratios were similar in the AD and control cells. The rate of conversion of α-keto[1-¹⁴C]glutarate to ¹⁴CO₂ was slightly but not statistically significantly less in the AD than in the control cells. The similarity in levels of glutamate and other amino acids in intact AD and control cells may be due in part to the high glutamate and glutamine content of the culture medium used. The similar incorporation of label derived from [¹³N]ammonia into glutamate/aspartate and the similar levels of α-ketoglutarate in AD and control cells may be due in part to the fact that KGDHC is not the rate-limiting enzyme for the tricarboxylic acid cycle in fibroblasts, although it does appear to be rate-limiting in brain. Cultured cells are established tools for identifying genetic and molecular defects in the host, but the studies above show the limitations in using them as a model of brain cell metabolism.

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“…The changes of some peptidase levels have been observed in the brain of AD patients (52,53). Although CCK-8S-LI and SS-LI levels were influenced in the drug-treated rats (Table 1), no change was observed in the immunoreactivities of PSA and EP24.15 and the APB-like and LAP-like enzyme activities in the present study (Fig.…”

Section: The Relation Between Neuropeptide and Their Degrading Enzymementioning

confidence: 43%

Changes in the Levels of Neuropeptides and Their Metabolizing Enzymes in the Brain Regions of Nucleus Basalis Magnocellularis-Lesioned Rats

2003

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Abstract. The regulation mechanism of the interrelation between neuropeptides and their metabolizing enzymes in in vivo tissues is still not clear. In the present report, we attempted to measure the levels of neuropeptides and their enzymes in the frontal cortex, hippocampus, and striatum of the rat that had been bilaterally lesioned by the infusion of ibotenic acid or amyloid b-peptide 25 -35 (Ab 25 -35) into the nucleus basalis magnocellularis. In the drug-treated rats, at two weeks after the infusion, the decrease of somatostatin-like immunoreactivity (SS-LI) and the increase of cholecystokinin-8S-LI were found in some brain regions relative to vehicletreated rats. The immunoreactivities of endopeptidase 24.15 and puromycin-sensitive aminopeptidase and the leucine aminopeptidase-and aminopeptidase B-like enzyme activities did not change in the three brain regions, suggesting that the levels of those peptide-degrading enzymes do not correlate with the changes of the neuropeptide levels. The decrease of subtilisin-like proprotein convertase (SPC)-like enzyme activity was found in the hippocampus of the Ab25 -35-treated rats. The SS mRNA level decreased in the hippocampus in parallel with decreases in the SS-LI level and SPC-like enzyme activity. The present data indicate that some of the neuropeptide-processing enzymes may contribute to the control of neuropeptide levels.

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Affected enzyme activities in Alzheimer's disease are sensitive to antemortem hypoxia

Cited by 52 publications

References 36 publications

Alpha-ketoglutarate dehydrogenase: a target and generator of oxidative stress

Alpha-ketoglutarate dehydrogenase: a target and generator of oxidative stress

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

Changes in the Levels of Neuropeptides and Their Metabolizing Enzymes in the Brain Regions of Nucleus Basalis Magnocellularis-Lesioned Rats

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