Abnormalities in muscarinic cholinergic receptors and their G-protein coupling systems in the cerebral frontal cortex in Alzheimer's disease

Abstract

Receptor binding assays and in vitro macroautoradiography were used to analyze muscarinic cholinergic receptors (MCR) in the cerebral frontal cortex of Alzheimer's disease (AD), senile dementia of Alzheimer type (SDAT), and age-matched control brains at autopsy. Total MCR binding, detected by [ 3H]quiniclinidyl benzilate binding, did not differ significantly between the 3 groups. The concentrations of M1 subtype (M1-R), detected by [ 3H]pirenzepine binding, and high affinity state MCRs, however, were significantly lower in AD than in control and SDAT frontal cortices. No differences were detected in the affinity of these receptors for their ligands. The MCRs in AD frontal cortex were more sensitive to the agonist carbachol than were control MCRs. Autoradiography revealed a complete destruction of the laminar distribution of MCR and M1-R in AD and SDAT frontal cortices. Forskolin and phorbol ester binding sites, used to analyze second messenger systems, were significantly and markedly reduced in AD frontal cortex. In addition, coupling between MCR and second messenger systems was supersensitive in AD frontal cortex. Our findings that there are alterations in the structural distribution of MCR as well as reductions and abnormalities in second messenger systems in AD cerebral frontal cortex, suggest that drug therapy with acetylcholine precursors, choline esterase inhibitors and muscarinic agonists cannot eliminate symptoms in dementia patients. Furthermore, they point out the need for techniques to diagnose the disease prior to disintegration of the neuronal network, and the need for therapies to delay or prevent the progression of structural changes.