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 sy nthetase is decreased in the cerebral cortices of brains affected by Alzhei mer's disease. It is difficult to discern the reason for this decrease beca use it is not known whether the cellular distribution of glutamine syntheta se is altered in Alzheimer's disease. Therefore the present study has used immunocytochemistry to compare the cellular distributions of glutamine synt hetase 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 sy nthetase is influenced by the distribution of senile plaques. It was found that glutamine synthetase expression in astrocytes is diminished in Alzheim er's disease, particularly in the vicinity of senile plaques. The most stri king finding of the present study was that glutamine synthetase was express ed in a subpopulation of pyramidal neurons in all six Alzheimer's diseased brains, whereas glutamine synthetase was not observed in any neurons from c ontrol brains. The changed expression of glutamine synthetase may be trigge red by toxic agents in senile plaques, a reduced noradrenergic supply to th e cerebral cortex, and increased brain ammonia levels. That such dramatic c hanges occur in the distribution of this critical, and normally stable enzy me, suggests that the glutamate-glutamine cycle is profoundly impaired in A lzheimer's disease. This is significant because impairments of the glutamat e-glutamine cycle are known to cause alterations of mood and behaviour, dis turbance of sleeping patterns, amnesia, confusion and reduced awareness. Si nce these behavioural changes are also seen in Alzheimer's disease, it is s peculated that they might be attributable to the reduced expression of glut amine synthetase or to impairments of the glutamate-glutamine cycle. (C) 20 00 Elsevier Science Ltd. All rights reserved.