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Decreased pyruvate dehydrogenase complex activity in Huntington and Alzheimer brain
Insights
Pyruvate dehydrogenase complex (PDHC) activity is reduced in brain areas affected by Huntington and Alzheimer diseases. This deficiency may contribute to the reduced brain metabolism seen in these neurodegenerative conditions.
Area of Science:
- Neuroscience
- Biochemistry
- Mitochondrial Function
Background:
- Huntington disease (HD) and Alzheimer disease (AD) are neurodegenerative disorders characterized by progressive neuronal loss.
- Reduced cerebral metabolic rate and blood flow are common features in dementing illnesses.
- The role of mitochondrial dysfunction, specifically pyruvate dehydrogenase complex (PDHC) activity, in these diseases is not fully understood.
Purpose of the Study:
- To investigate the activity of the pyruvate dehydrogenase complex (PDHC) in specific brain regions affected by Huntington disease and Alzheimer disease.
- To examine the relationship between PDHC activity and choline acetyltransferase (CAT) activity, a marker of cholinergic neurons.
- To assess PDHC activity in fibroblasts from individuals with Down syndrome (a risk factor for AD) and in fibroblasts from HD and AD patients.
Main Methods:
- Measurement of pyruvate dehydrogenase complex (PDHC) and choline acetyltransferase (CAT) activities in post-mortem brain tissue (caudate, putamen, hippocampus, frontal cortex) from patients with HD and AD.
- Assay of fumarase activity as an inner mitochondrial marker.
- Analysis of PDHC activity in cultured fibroblasts from patients with C-21 trisomy Down syndrome, HD, and AD.
Main Results:
- PDHC activity was reduced in affected brain areas of HD (caudate, putamen) and AD (frontal cortex) patients, correlating with low CAT activity in these regions.
- PDHC deficiency was also observed in the Huntington hippocampus, irrespective of CAT levels.
- Normal fumarase activity indicated preserved mitochondrial integrity. PDHC activity and activation were reduced in Down syndrome fibroblasts, but not in HD or AD fibroblasts.
Conclusions:
- Reduced PDHC activity may contribute to the pathophysiology of Huntington and Alzheimer diseases by impairing tissue oxidative capacity.
- The observed PDHC deficiency is likely a consequence rather than a primary defect in these neurodegenerative conditions.
- The findings suggest a link between impaired mitochondrial energy metabolism and the reduced cerebral metabolic rate characteristic of many dementing illnesses.
Abstract:
The activity of the pyruvate dehydrogenase complex (PDHC) was reduced in affected areas of brain from patients with Huntington disease (caudate, putamen) and Alzheimer disease (frontal cortex) where choline acetyltransferase (CAT) activity was low. PDHC was also deficient in an area (Huntington hippocampus) where CAT was not significantly reduced. The activity of fumarase, an inner mitochondrial marker, was normal in all areas examined. The activities of PDHC and CAT correlated well in caudate, putamen, and amygdala but not in hippocampus or frontal cortex. Both total activity and activation of PDHC were below normal in fibroblasts from 4 patients with C-21 trisomy Down syndrome, who are at very high risk to develop Alzheimer disease. However, no abnormality of PDHC was detected in Huntington or Alzheimer fibroblasts. Deficiency of PDHC may play a role in the pathophysiology of Huntington and Alzheimer diseases, although it does not appear to be a primary defect. Loss of tissue oxidative capacity may relate to the reduction in cerebral metabolic rate and blood flow which are characteristic of many dementing illnesses.