α‐ketoglutarate dehydrogenase in alzheimer brains bearing the APP670/671 mutation

Abstract

Alzheimer's disease (AD) is associated with a striking reduction in the activity of the alpha-ketoglutarate dehydrogenase complex (KGDHC). The deficiency occurs in brains from AD patients of undefined etiology, and in fibroblasts from both sporadic and familial AD cases. To further assess the nature of the abnormality of KGDHC in AD, KGDHC activities and immunoreactivities were analyzed in brains from AD patients bearing the Swedish APP670/671 mutation. This gene defect causes overproduction of the amyloid beta peptide. KGDHC activities were reduced by 55 to 57% compared with control values in the mutation-bearing AD cases in the medial temporal and superior frontal cortices. The immunochemical levels of KGDHC subunits Elk (-51%) and E2k (-76%) declined, whereas E3 concentrations were unchanged. The results suggest that mitochondrial dysfunction is a part of the pathophysiological process in AD even when the primary pathogenic cause is nonmitochondrial.

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

“…The change in the a-KGDH activity was as consistent and characteristic as the abnormal amyloid metabolism (Gibson et al 1988(Gibson et al , 1998. a-KGDH in fibroblasts from patients with presenilin-1 mutation was either reduced (Sheu et al 1994) or had increased vulnerability to oxidative stress .…”

Reduction in the E2k Subunit of the α-Ketoglutarate Dehydrogenase Complex Has Effects Independent of Complex Activity

“…Total RNA was isolated using TRIzol reagent (Invitrogen) according to the supplier's instructions. This was followed by first strand cDNA synthesis using the First Strand cDNA synthesis kit for RT-PCR (AMV) (Roche Applied Science, Indianapolis, IN) with oligo-p(dT) 15 as primer. The desired insert of E2k was amplified from the synthesized cDNA with TaqDNA polymerase using a pair of gene-specific primers (P E2kS 5Ј-AGGTGGGAGAAAGCTGTTGGAG-3Ј/P E2kAS 5Ј-TCCCGATGTTCT-GAACGCAGAC-3Ј).…”

“…tivities (Ϫ55% to Ϫ57%) and in the immunoreactivities of E1k (Ϫ51%) and E2k (Ϫ76%) but not E3 (15). Oxidative stress also selectively alters the immunoreactivity of the subunits.…”

“…Whether the protein levels (i.e. immunoreactivity) of the three subunits of KGDHC decline with disease is variable in both genetic and sporadic forms of the AD (15,31). The three subunits also show a selective response to oxidative stress (32).…”

Human 2-Oxoglutarate Dehydrogenase Complex E1 Component Forms a Thiamin-derived Radical by Aerobic Oxidation of the Enamine Intermediate

“…The results indicate that E1o-h does produce both the ThDPenamine radical and superoxide/H 2 O 2 . Generation of superoxide/H 2 O 2 by E1o-h may have pathological relevance, especially under conditions of genetic deficiencies of the E2o-h due to mutations (25), polymorphism (26), or down-regulation (27,28). In cultured human embryonic kidney cells, the reduction in E2o-h level augmented ROS generation and cell death (27).…”