Expression of nicotinic acetylcholine receptor subunits in the cerebral cortex in Alzheimer's disease: histotopographical correlation with amyloid plaques and hyperphosphorylated-tau protein

Impairment of cholinergic transmission and decreased numbers of nicotinic b inding sites are well-known features accompanying the cognitive dysfunction seen in Alzheimer's disease (AD). In order to elucidate the underlying cau se of this cholinoceptive dysfunction, the expression of two pharmacologica lly different nicotinic acetylcholine receptor (nAChR) subunits (alpha 4, a lpha 7) was studied in the cerebral cortex of Alzheimer patients as compare d to controls. Patch-clamp recordings of 14 dissociated neurons of control cortices showed responses suggesting the existence of alpha 4- and alpha 7- containing functional nAChRs in the human cortex. In cortices of Alzheimer patients and controls, the pattern of distribution and the number of alpha 4 and alpha 7 mRNA-expressing neurons were similar, whereas at the protein level a decrease in the density of alpha 4- and alpha 7-expressing neurons of approximate to 30% was observed in Alzheimer patients. The histotopograp hical correlation of nAChR expression with accompanying pathological change s, e.g. accumulation of hyperphosphorylated-tau (HP-tau) protein and beta-a myloid showed that neurons in the vicinity of beta-amyloid plaques bore bot h nAChR transcripts. Neurons heavily labelled for HP-tau, however, expresse d little or no alpha 4 and alpha 7 mRNA. These results point to an impaired synthesis of nAChRs on the protein level as a possible cause of the cholin oceptive deficit in AD. Further investigations need to elucidate whether in teractions of HP-tau with nAChR mRNA, or alterations in the quality of alph a 4 and alpha 7 transcripts give rise to decreased protein expression at th e level of individual neurons.