{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T21:27:54Z","timestamp":1782422874406,"version":"3.54.5"},"reference-count":51,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2004,10,8]],"date-time":"2004-10-08T00:00:00Z","timestamp":1097193600000},"content-version":"vor","delay-in-days":3874,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Annals of Neurology"],"published-print":{"date-parts":[[1994,3]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>To test whether previously demonstrated reductions in the activity of the \u03b1\u2010ketoglutarate dehydrogenase complex (KGDHC) in Alzheimer's disease (AD) brain also occur in morphologically normal AD tissues, we examined KGDHC in cultured skin fibroblasts from patients with familial AD (FAD). KGDHC activity was reduced by 44% in the FAD cells (<jats:italic>p<\/jats:italic> &lt; 0.002) from the 4 families studied, including a within\u2010kindred comparison of affected and escape subjects in the chromosome 14q24.3\u2010linked Nova Scotia kindred. The activities of several other glutamate\u2010 and glutamine\u2010metabolizing enzymes were normal in the FAD cells, as was the activity of another mitochondrial multienzyme dehydrogenase complex, that for pyruvate. Mixing experiments indicated that the abnormality of KGDHC activity in FAD fibroblasts was not due to an inhibitor or to excess protease activity. KGDHC is a complex of three proteins. Immunoblots for the E2k component under conditions of optimal protease inhibition revealed the expected 46\u2010kd species in both AD and non\u2010AD fibroblasts, but the patient cells also regularly contained an additional 29\u2010kd species that was absent or present in minimal amounts in the controls. Immunoblotting demonstrated no abnormalities in the E1k and E3 components. Other studies indicate that the human gene for E2k resides on chromosome 14q24.3, in a region associated with FAD in a number of families including the KGDHC\u2010deficient Nova Scotia kindred. The persistence of abnormalities in KGDHC and particularly in its E2k component in FAD fibroblasts indicates that abnormalities of this autosomally coded nuclear component are an intrinsic part of the AD process, and the possible role of this abnormality in the pathogenesis of AD is discussed.<\/jats:p>","DOI":"10.1002\/ana.410350311","type":"journal-article","created":{"date-parts":[[2005,1,1]],"date-time":"2005-01-01T14:35:07Z","timestamp":1104590107000},"page":"312-318","source":"Crossref","is-referenced-by-count":83,"title":["Abnormality of the \u03b1\u2010ketoglutarate dehydrogenase complex in fibroblasts from familial Alzheimer's disease"],"prefix":"10.1002","volume":"35","author":[{"given":"Kwan\u2010Fu Rex","family":"Sheu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arthur J. 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