Regional distribution of nicotinic receptor subunit mRNAs in human brain:: comparison between Alzheimer and normal brain

The regional expression of mRNA for the nicotinic acetylcholine receptor (nAChR) subunits alpha 3, alpha 4 and alpha 7 was examined in postmortem brain tissues from controls and patients with Alzheimer's disease (AD) by using quantitative RT-PCR. In parallel, the numbers of nAChRs were measured by receptor binding. Relative quantification of the nAChR gene transcripts in control brains showed that expression of alpha 3 was highest in the parietal cortex, frontal cortex and hippocampus, and lower in the temporal cortex and cerebellum. The highest level of alpha 4 mRNA was found in the temporal cortex and cerebellum, while alpha 7 mRNA was equally distributed in all brain regions except for hippocampus where it was less abundant. In comparison with AD brains, no differences in the expression of alpha 3 and alpha 4 in the temporal cortex, hippocampus and cerebellum were found. The level of alpha 7 mRNA was significantly higher in the hippocampus of AD brains compared to controls. The binding sites for [H-3] epibatidine and [H-3] nicotine in the temporal cortex and [I-125] alpha-bungarotoxin in hippocampus were significantly decreased in AD patients compared to controls. Saturation analysis of [3H] epibatidine binding revealed two classes of binding sites, with a significant reduction of the higher affinity epibatidine binding sites in the temporal cortex of AD brain. The results show that there is a regional distribution of the expression of the different nAChRs subunits in human brain. The findings that the alpha 3 and alpha 4 mRNA levels were not changed in AD brains suggest that the loss of higher affinity epibatidine binding sites observed in AD patients cannot be attributed to alternations at the transcriptional level of the alpha 3 and alpha 4 genes and that causes have to be searched for at the translational and/or posttranslational level. The increased mRNA level of alpha 7 previously found in lymphocytes, and now also in the hippocampus of AD patients, indicate that subunit specific changes in gene expression of nAChRs is associated with AD. (C) 1999 Elsevier Science B.V. All rights reserved.