Brain α‐Ketoglutarate Dehydrotenase Complex Activity in Alzheimer's Disease

Abstract

We measured the activity of the alpha-ketoglutarate dehydrogenase complex (alpha-KGDHC), a rate-limiting Krebs cycle enzyme, in postmortem brain samples from 38 controls and 30 neuropathologically confirmed Alzheimer's disease (AD) cases, in both the presence and absence of thiamine pyrophosphate (TPP), the enzyme's cofactor. Statistically significant correlations between brain pH and lactate levels and alpha-KGDHC activity in the controls were observed, suggesting an influence of agonal status on the activity of alpha-KGDHC. As compared with the controls, mean alpha-KGDHC activity, with added TPP, was significantly (p < 0.005) reduced in AD brain in frontal (-56%), temporal (-60%), and parietal (-68%) cortices, with the reductions (-25 to -53%) in the occipital cortex, hippocampus, amygdala, and caudate failing to reach statistical significance. In the absence of exogenously administered TPP, mean alpha-KGDHC activity was reduced to a slightly greater extent in all seven AD brain areas (-39 to -83%), with the reductions now reaching statistical significance in the four cerebral cortical areas and hippocampus. A statistically significant negative correlation was observed between alpha-KGDHC activity and neurofibrillary tangle count in AD parietal cortex, the brain area exhibiting the most marked reduction in enzyme activity; this suggests that the enzyme activity reduction in AD brain may be related to the disease process and severity. In each brain area examined, TPP produced a greater stimulatory effect on alpha-KGDHC activity in the AD group (23-280% mean stimulation) as compared with the controls (-4 to +50%); this TPP effect could be explained by reduced endogenous TPP levels in AD brain.(ABSTRACT TRUNCATED AT 250 WORDS)

Neuronal Pyruvate Carboxylation Supports Formation of Transmitter Glutamate

“…Reagents for the enzyme assays were from Sigma. Malic enzyme, citrate synthase, f umarase, and ␣-ketoglutarate dehydrogenase were analyzed as described (Hill and Bradshaw, 1969;Hsu and Lardy, 1969;Srere, 1969;Mastrogiacomo et al, 1993) in homogenates of cell cultures obtained by harvesting cells in 1 ml sucrose, 0.32 M, or in 5% homogenates of rat striatum in sucrose, 0.32 M. Succinate dehydrogenase activity was analyzed by formation of formazan from a tetrazolium salt (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide; Kugler et al, 1988); formazan was extracted and assayed spectrophotometrically at 570 nm (Hansen et al, 1989).…”

Role of thiamine in Huntington’s disease pathogenesis: In vitro studies

“…26 Mastrogiacomo et al measured the activity of KGDHC in postmortem brain samples from confirmed AD cases in both the presence and absence of TPP. 27 In each brain area examined, TPP produced a greater stimulatory effect on KGDHC activity in AD group as compared with the controls. The consequences of thiamine deficit were discussed also in non-CNS tissues.…”

Low Thiamine Diphosphate Levels in Brains of Patients with Frontal Lobe Degeneration of the Non‐Alzheimer's Type

“…Alzheimer's disease patients who have~=20% decreased brain TDP levels (Mastrogiacomo et al, 1996) also have reduced TDP-dependent enzyme activities (Mastrogiacomo et al, 1993;Eisinger et al, 1994;Héroux et al, 1996). One of these enzymes, aKGDHC, is a rate-limiting enzyme of the citric acid cycle and decreased enzyme activities may thus lead to a slowdown of brain oxidative metabolism.…”

“…Recently, our group (Mastrogiacomo et al, 1996) as well as Butterworth's group (Héroux et al, 1996) reported a 20% decrease in TDP levels in the postmortem cortex of Alzheimer' s disease patients. This might be related to the low activities of TDPdependent enzymes observed in the cortex of these patients (Mastrogiacomo et al, 1993;Héroux et al, 2006L. BETI'ENDORFF ET AL 1996.…”