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dependent phosphokinase C, with the result, cell death. If this were to occur periodically, with a decrease in bioenergy, then there would be a gradual decline in neurons, a decrease in receptors, an increase in glutamate, and possibly an increase in citric acid cycle intermediates.
In cultured fibroblasts and cultured neuronal cells, glutamate interferes with the transport of cystine. As a result, glutathione becomes depleted rapidly and fibroblasts become sensitized to free-radical damage. The cells degenerate and die in less than 24 hours. The cells of the hippocampus are subjected to a larger concentration of free radicals because of local alterations in superoxide dismutase and may be preferentially subject to oxidative stress and selective vulnerability. Furthermore, oxidative products would reduce the glutamine synthetase metabolism of glutamate and increase glutamate's concentration.25'26
In aging and hypoxia, there is a reduction of calcium uptake into the presynaptic terminals and into nerve-ending mitochondria. The results are a greater synaptic concentration of calcium, a release of glutamate, and a large postsynaptic influx of calcium leading to cell death. Or, intracellular calcium may be freed from storage sites and increased, as the result of some unidentified protein, such as occurs in the acquired immunodeficiency syndrome.
Alzheimer's disease may result from an alteration in the postsynaptic receptor. There may be a protein agonist--either toxic, infective, or autoimmune--that stimulates the receptor, or a separate receptor subunit mutation. Both would lead to amplified calcium influx and cell death.
Is AD a consequence of aging? Will it ultimately occur as the life cycle is extended? Or is it the effect of some toxin, infection, or autoimmune disease that interferes with the glutamate uptake transport carrier?
The lesions in AD occur in the glutamatergic pathways; glutamate neurotoxicity can account for all these lesions. Glutamate causes the formation of neurofibrillary tangles, amy-bid plaques, decreases in RNA, loss of dendrites, and death. Glutamate is increased in response to acute and chronic insults, and the aged brain appears to be more sensitive to the evolution of deficits resulting from these metabolic abuses over the whole life span. This increment coupled to a decrease in glucose utilization will render the neuron sensitive to glutamate neurotoxicity and lead to the development of AD.
Comment
In this pilot study, the concentrations of plasma glutamate and its metabolites and enzymes were compared in control subjects and patients with moderate AD in a nursing home setting. These results demonstrate the first known significant increase in plasma aspartate, glutamate, glutamate dehydrogenase, and a-ketoglutarate concentrations in AD patients. A discriminant analysis number, which classifies perfectly, and has sensitivity and specificity of (Continued on page 145)
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