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An abnormality of the 2-oxoglutarate dehydrogenase in Alzheimer's disease brain and fibroblast. Kichiko KOIKE 1 , Tadayasu HIRAOKA 1 , Yutaka NAKAULA 1 , Ryozo KUWANO 2 , Masahiko KOIKE 1 , John P BIass 3 , Kwan-Fu R Sheu 3 , Gary E Gibson 3 1Department of Pathological Biochemistry, Atomic Disease Institute, Nagasaki University School of Medicine 2Research Laboratory for Molecular Genetics, Niigata University 3Altschul Laboratory for Dementia Research, Cornell University Medical College at Burke Medical Research Institute pp.1023-1030
Published Date 1993/12/10
DOI https://doi.org/10.11477/mf.1431900396
  • Abstract
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 Preliminary studies of the isolation of porcine brain mitochondria and synaptic vesicles and their thiamin pyrophosphate (TPP)-dependent enzyme (TPP enzyme) activities suggest the wide distribution of the pyruvate and 2-oxoglutarate dehydrogenase (PDH and OGDH) complexes in brain mitochondria. These complexes appear to be relatively concentrated in the cholinergic synaptic ending.

 Because of clinical and neuropathological overlap between the characteristics of dementia of Alzheimer's disease (AD) and of Wernicke-Korsakoff syndrome caused with thiamin deficiency the TPP enzymes have been studied in AD brain, its skin fibroblast and platelets. The activities of mitochondrial PDH and OGDH complexes and cytosolic transketolase (TK) are dramatically reduced in AD brain. The most marked reduction is in the OGDH complex to less than 20% of the control. In cultured skin fibroblast from familial AD the OGDH complex activity is reduced 44% of the control. We have cloned and sequenced of the human cDNA encoding OGDH, which is one of three component enzymes of the OGDH complex. RNA blot analysis was failed because of too low concentration of the OGDH mRNA in AD and non-AD fibroblasts. Therefore the mRNA is immediately reverse-transcripted to cDNA by the reverse transcriptase and amplified specific 638 base pair (bp)-segment (nt. 76-713 of OGDHcDNA) with specific primers by PCR. PCR products are electrophoresed, transfered onto membrane, and detected with radiolabeled cDNA probe. Level of the OGDH-mRNA in AD fibroblast was consistently reduced, suggesting abnormality of the OGDH gene or its primary structure. The present results indicate that mitochondrial abnormalities in AD are not likely to be a consequence of the disease process, but are an intrinsic part of it.


Copyright © 1993, Igaku-Shoin Ltd. All rights reserved.

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電子版ISSN 1882-1243 印刷版ISSN 0001-8724 医学書院

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