Enzymes of the Tricarboxylic Acid Cycle in Neurodegeneration

Diminished brain metabolism and oxidative stress are characteristic features of Alzheimer's disease (AD). The mechanisms underlying these changes are as yet poorly defined. Our recent studies indicate that a marker of mitochondrial damage,  the α‑ketoglutarate dehydrogenase complex (KGDHC), correlates at least as well with clinical disability as do plaque and tangle counts. KGDHC and several other mitochondrial enzymes are known to be sensitive to reactive oxygen species (ROS).

These studies test the hypothesis that: impairment of select mitochondrial enzymes by ROS is an important component of the cascade of events that leads to diminished metabolism and to the cognitive deficits in AD. This hypothesis will be tested on human autopsy brains collected by our collaborators at the Mt Sinai (N.Y.) ADRC, who have collected several hundred samples of brain from patients whose pre‑terminal neuropsychological status has been determined using the Clinical Dementia Rating (CDR). Quantitative markers of oxidative stress and activities of specific mitochondrial enzymes will be compared to clinical status (CDR) and to markers of AD pathology including plaque and tangle counts, by refined statistical methods. Tissue culture models will also be used, so as to do mechanistic experiments on the effects of specific ROS on the activities of the same mitochondrial enzymes examined in the necessarily co-relational studies of human autopsied brain.

The models will be: (1) cultured fibroblasts from AD patients, to test the effects of ROS on cells which have the same genetic background as that in which the disease is expressed; (2) culture models of neurons, the most vulnerable cell type in AD brains. These models will also provide systems to test the efficacy of approaches to limit or reverse the changes in mitochondrial enzymes due to ROS. Thus, these studies will not only help clarify mechanisms in AD, but also have direct implications for the development of new therapies.