Brain α‐Ketoglutarate Dehydrotenase Complex Activity in Alzheimer's Disease

We measured the activity of the a-ketoglutarate dehydrogenase complex (α-KGDHC), a rate-limiting Krebs cycle enzyme, in postmortem brain samples from 38 controls and 30 neuropathologically confirmed Alzheimer's disease (AD) cases, in both the presence and absence of thiamine pyrophosphate (TPP), the enzyme's cofactor. Statistically significant correlations between brain pH and lactate levels and α-KGDHC activity in the controls were observed, suggesting an influence of agonal status on the activity of α-KGDHC. As compared with the controls, mean α-KGDHC activity, with added TPP, was significantly (p < 0.005) reduced in AD brain in frontal (-56%), temporal (-60%), and parietal (-68%) cortices, with the reductions (-25 to -53%) in the occipital cortex, hippocampus, amygdala, and caudate failing to reach statistical significance. In the absence of exogenously administered TPP, mean a-KGDHC activity was reduced to a slightly greater extent in all seven AD brain areas (-39 to -83%), with the reductions now reaching statistical significance in the four cerebral cortical areas and hippocampus. A statistically significant negative correlation was observed between α-KGDHC activity and neurofibrillary tangle count in AD parietal cortex, the brain area exhibiting the most marked reduction in enzyme activity; this suggests that the enzyme activity reduction in AD brain may be related to the disease process and severity. In each brain area examined, TPP produced a greater stimulatory effect on α-KGDHC activity in the AD group (23–280% mean stimulation) as compared with the controls (-4 to ±50%); this TPP effect could be explained by reduced endogenous TPP levels in AD brain. Reduced brain α-KGDHC activity could be consequent to loss of neurons preferentially enriched in α-KGDHC, a premortem reduction in TPP levels (which may have affected enzyme stability), elevated brain levels of the α-KGDHC inhibitor ammonia, or an actual failure in the expression of the gene encoding the enzyme. We suggest that a defect in this key Krebs cycle enzyme could contribute to an impairment of cerebral energy metabolism and the brain dysfunction in AD.