Regional alterations in m., muscarinic receptor-g protein coupling in alzheimer's disease

Abstract

Previous studies examining the functional status of cortical muscarinic cholinergic M, receptors have demonstrated an impairment in receptor-G protein coupling in Alzheimer's disease (AD) as measured by the inability of the receptor to form a high affinity agonist binding site. In order to investigate whether this alteration was a global phenomenon or a regional specific defect in signal transduction, we examined agonist binding at M, receptors in three brain areas (superior frontal cortex, Brodmann areas 8 and 9; primary visual cortex, Brodmann area 17; and the dorsal striatum) within the same brain in controls and moderate to severe AD cases. Competition binding studies using the M, antagonist 3H-pirenzepine (4 nM) in the presence of varying concentrations of the cholinergic agonist carbachol (50 nM to 1 mM) were performed in the presence and absence of GppNHp (100 u, M), a non-hydrolyzable analog of GTP. In control membrane preparations, computer-assisted analysis of antagonist-agonist competition curves revealed that M, receptor agonist binding fit a two site model with high and low affinity states in all three brain areas in the absence of GppNHp but only a single site in the presence of GppNHp. This is consistent with the ternary complex model of G protein-linked receptors. In contrast, curves obtained from both cortical regions from AD brains fit a single site model with low affinity in the presence or absence of GppNHp. On the other hand, agonist binding data obtained from the dorsal striatum of AD cases exhibited a two site fit, similar to that seen in controls. The loss of M, high affinity agonist binding observed in AD is not a global defect, rather it appears to be restricted to discrete regions that are correlated with a relative abundance of neuritic core plaques but not diffuse plaques or neurofibrillary tangles. © 1995 by the American Association of Neuropathologists.