Neuronal expression of glutamine synthetase in Alzheimer's disease indicates a profound impairment of metabolic interactions with astrocytes

A considerable body of evidence indicates that the activity of glutamine synthetase is decreased in the cerebral cortices of brains affected by Alzheimer's disease. It is difficult to discern the reason for this decrease because it is not known whether the cellular distribution of glutamine synthetase is altered in Alzheimer's disease. Therefore the present study has used immunocytochemistry to compare the cellular distributions of glutamine synthetase in the inferior temporal cortices of six Alzheimer's diseased brains and six age-matched, non-demented brains. Double-label immunocytochemistry has been used to examine whether the distribution of cellular glutamine synthetase is influenced by the distribution of senile plaques. It was found that glutamine synthetase expression in astrocytes is diminished in Alzheimer's disease, particularly in the vicinity of senile plaques. The most striking finding of the present study was that glutamine synthetase was expressed in a subpopulation of pyramidal neurons in all six Alzheimer's diseased brains, whereas glutamine synthetase was not observed in any neurons from control brains. The changed expression of glutamine synthetase may be triggered by toxic agents in senile plaques, a reduced noradrenergic supply to the cerebral cortex, and increased brain ammonia levels. That such dramatic changes occur in the distribution of this critical, and normally stable enzyme, suggests that the glutamate-glutamine cycle is profoundly impaired in Alzheimer's disease. This is significant because impairments of the glutamate-glutamine cycle are known to cause alterations of mood and behaviour, disturbance of sleeping patterns, amnesia, confusion and reduced awareness. Since these behavioural changes are also seen in Alzheimer's disease, it is speculated that they might be attributable to the reduced expression of glutamine synthetase or to impairments of the glutamate-glutamine cycle.