Mitochondrial function in brain tissue in primary degenerative dementia.

Previous in vitro and in vivo studies of the brain in Alzheimer's disease indicated alterations in metabolism related to energy production although the relationships between these changes remains obscure. To help resolve this issue, in vitro oxygen uptake by homogenates of fresh samples of frontal neocortex from patients with dementia and neurosurgical controls has been examined as a measure of energy-related metabolism and mitochondrial function. Maximal respiratory rates (measured in the presence of an uncoupling agent) were similar for samples from 7 controls, 5 patients with Alzheimer's disease and two patients diagnosed clinically as Pick's disease, suggesting that there was little or no effect of these dementias on the maximal metabolic capacity of the tissue. However, under some conditions producing sub-maximal metabolic activity (which are of potentially greater physiological relevance) oxygen uptake rates were significantly elevated in the dementia group. The ratio of oxygen uptake rates in the presence and absence of ADP was significantly reduced (to 58% of control; P less than 0.02) for the dementia patients compared with controls, possibly indicative of partial mitochondrial uncoupling. These results indicate metabolic changes expressed in vitro which may be relevant to the pathogenesis of Alzheimer's disease and some related dementias.

Effects of postdecapitative ischemia on mitochondrial respiration in brain tissue homogenates.

Mitochondria isolated from ischemic brain characteristically show changes in respiratory function. As conventional procedures for mitochondrial isolation yield a subpopulation of the total population and require extensive manipulation, it is unclear to what extent these changes are representative of mitochondria in the unfractionated tissue. We previously showed that the oxygen uptake by unfractionated forebrain homogenates, measured under two different sets of incubation conditions, provided information on some aspects of the respiratory activity of both the free and synaptosomal pools of mitochondria. Forebrain homogenates from animals subjected to 30 min of postdecapitative ischemia exhibited large reductions in oxygen uptake rates measured in a high K+ (mitochondrial) buffer in the presence of either ADP (44% of control values) or an uncoupling agent (45% of control values). These reductions in respiratory activity were comparable to alterations observed under the same conditions for mitochondria isolated from the ischemic brains. Similar alterations were seen in homogenates from three subregions: neocortex, hippocampus, and striatum. In a physiological buffer, in which oxygen uptake by homogenates largely resulted from activity of mitochondria within synaptosomes, there was little or no change in basal glucose-supported rates (79-96% of control values) and small reductions in maximal rates (63-81% of control values) measured in the presence of an uncoupling agent. These results suggest that alterations of respiratory function seen in isolated free mitochondria provide appropriate estimates of the dysfunction in the total free mitochondrial pool but that synaptosomal mitochondria may be less affected. Measurements of respiratory function of isolated synaptosomes from ischemic tissue provided further support for the relative preservation of synaptosomal mitochondria during ischemic insult.

Altered metabolic properties of cultured skin fibroblasts in Alzheimer's disease.

Alzheimer's disease is associated with selective neuronal loss, the cause of which is undetermined. Evidence indicating a predisposing genetic factor associated with this disease suggests that important alterations may be expressed in tissues other than the brain. Because abnormal glucose and energy-related metabolism have been identified in both in vivo and in vitro studies of brain, we conducted a study to examine related measures in cultured skin fibroblasts from six patients with Alzheimer's disease and seven age-matched controls. After 60 minutes' incubation, the production of 14CO2 from [U-14C]glucose and lactate production were significantly higher in the cells from the group of patients with Alzheimer's disease. The increase of 14CO2 production, but not the production of lactate, was most evident after a more rapid period of metabolic activity in the first 10 minutes of incubation. By contrast, 14CO2 production from [U-14C]glutamine, which is probably the major substrate of oxidative metabolism in these cells, was significantly reduced in the Alzheimer's disease cells following longer (120-minute) incubations. Oxygen uptake by cell suspensions was also significantly reduced in the group with Alzheimer's disease. These results indicate that complex metabolic differences are expressed in nonneural tissues from some patients with Alzheimer's disease and may provide important clues to the pathogenesis of this disorder.