Brain protein and α‐ketoglutarate dehydrogenase complex activity in alzheimer‐s disease

Abstract

To determine whether the reduction in brain alpha-ketoglutarate dehydrogenase complex activity in Alzheimer's disease (AD) is associated with an abnormality in one of its three constituent enzyme subunits, we measured protein levels of alpha-ketoglutarate dehydrogenase (El), dihydrolipoamide succinyltransferase (E2), and dihydrolipoamide dehydrogenase (E3), in postmortem brain of 29 patients with AD (mean age, 73 years; age range of onset, 50-78 years) and 29 control subjects. In the AD group protein levels of all three subunits were significantly reduced by 23 to 41% in the temporal cortex, whereas in the parietal cortex (El: -28%; E3: -32%) and hippocampus (E3: -33%) significant changes were limited to El and E3. alpha-Ketoglutarate dehydrogenase complex activities were more markedly reduced (by 46-68%) and did not correlate with protein levels, suggesting that decreased enzyme activity cannot be primarily explained by loss of alpha-ketoglutarate dehydrogenase complex protein. We did not find two E2 immunoreactive forms in the brain of any patient, as has been reported in fibroblasts of patients with very-early-onset chromosome 14-linked AD. We conclude that brain protein and activity levels of alpha-ketoglutarate dehydrogenase complex are reduced in patients with AD who have onset after 50 years and suggest that these changes, which are also observed in other human brain disorders, may represent a nonspecific consequence of different neurodegenerative processes. Nevertheless, reduced levels of this rate-limiting enzyme of the Krebs cycle could contribute to the brain neurodegenerative mechanisms of AD.

Differential Effects of Mitochondrial Heat Shock Protein 60 and Related Molecular Chaperones to Prevent Intracellular β-Amyloid-induced Inhibition of Complex IV and Limit Apoptosis

“…Neurons require a constant glucose supply for the generation of ATP, and mitochondrial dysfunction in AD includes the diminished activities of ATP regulating enzymes, creatine kinase, PDH, and ␣-KGDH (47)(48)(49). The mechanism of their inhibition may proceed through intracellular ␤-amyloid-mediated free radical generation and indirect oxidative damage or, alternatively, through direct interaction with 〈␤-(1-42).…”

Zn2+ Inhibits α-Ketoglutarate-stimulated Mitochondrial Respiration and the Isolated α-Ketoglutarate Dehydrogenase Complex

“…2 Oxidative energy metabolism is impaired in many neurodegenerative disorders (22)(23)(24). In particular, KGDHC activity in brain is reduced in Alzheimer's disease and a number of other neurodegenerative disorders (25,26,29,67), but the possible relationship of the enzyme deficiency to Zn 2ϩ levels in these conditions has not yet been explored. The decrease in KGDHC activity in Alzheimer's disease brain has been reported to exceed the decrease in KGDHC protein (67).…”

“…In particular, KGDHC activity in brain is reduced in Alzheimer's disease and a number of other neurodegenerative disorders (25,26,29,67), but the possible relationship of the enzyme deficiency to Zn 2ϩ levels in these conditions has not yet been explored. The decrease in KGDHC activity in Alzheimer's disease brain has been reported to exceed the decrease in KGDHC protein (67). Imbalances in the distribution of Zn 2ϩ (63)(64)(65) in Alzheimer's disease brain may contribute to the loss of KDGHC activity.…”

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

“…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).…”