Normal glutamate metabolism in Alzheimer's disease fibroblasts deficient in alpha-ketoglutarate dehydrogenase complex activity.
Deficient activity of the alpha-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 alpha-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 alpha-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.
Cooper
A L
AL
Department of Biochemistry, Cornell University Medical College, New York, USA.
Sheu
K F
KF
Blass
J P
JP
D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D003653:Decarboxylation; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism*; D006801:Humans; D007655:Ketoglutarate Dehydrogenase Complex / Q000378:metabolism*; D007656:Ketoglutaric Acids / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009590:Nitrogen Radioisotopes; D012016:Reference Values
D007656:Ketoglutaric Acids; D009590:Nitrogen Radioisotopes; D018698:Glutamic Acid; D007655:Ketoglutarate Dehydrogenase Complex