Expression of nicotinic acetylcholine receptors in Alzheimer's disease: postmortem investigations and experimental approaches

Nicotinic ligand binding studies have shown rather early that the cholinoce ptive system is affected in Alzheimer's disease (AD). Today, molecular hist ochemistry enables one to study the nicotinic acetylcholine receptor (nAChR ) subunit expression on the cellular level in human autopsy brains, in anim al models and in in vitro approaches, thus deciphering the distribution of nAChRs and their role as potential therapeutic targets. The studies on the nAChR expression in the frontal and temporal cortex of AD patients and age- matched controls could demonstrate that both, the numbers of alpha 4- and a lpha 7-immunoreactive neurons and the quantitative amount, in particular of the alpha 4 protein, were markedly decreased in AD. Because the number of the corresponding mRNA expressing neurons was unchanged these findings poin t to a translational/posttranslational rather than a transcriptional event as an underlying cause. This assumption is supported by direct mutation scr eening of the CHRNA4 gene which showed no functionally important mutations. To get more insight into the underlying mechanisms, two model systems - or ganotypic culture and primary hippocampal culture - have been established, both allowing to mimic nAChR expression in vitro. In ongoing studies the po ssible impact of beta-amyloid (A beta) on nAChR expression is tested. Preli minary results obtained from primary cultures point to an impaired nAChR ex pression following A beta exposure. (C) 2000 Elsevier Science B.V. All righ ts reserved.