REGIONAL ALTERATIONS IN M(1) MUSCARINIC RECEPTOR-G PROTEIN COUPLING IN ALZHEIMERS-DISEASE

Previous studies examining the functional status of cortical muscarini c cholinergic M(1) receptors have demonstrated an impairment in recept or-G protein coupling in Alzheimer's disease (AD) as measured by the i nability of the receptor to form a high affinity agonist binding site. In order to investigate whether this alteration was a global phenomen on or a regional specific defect in signal transduction, we examined a gonist binding at M(1) receptors in three brain areas (superior fronta l cortex, Brodmann areas 8 and 9; primary visual cortex, Brodmann area 17; and the dorsal striatum) within the same brain in controls and mo derate to severe AD cases. Competition binding studies using the M(1) antagonist H-3-pirenzepine (4 nM) in the presence of varying concentra tions of the cholinergic agonist carbachol (50 nM to 1 mM) were perfor med in the presence and absence of GppNHp (100 mu M), a non-hydrolyzab le analog of GTP. In control membrane preparations, computer-assisted analysis of antagonist-agonist competition curves revealed that M(1) r eceptor agonist binding fit a two site model with high and low affinit y 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 ter nary complex model of G protein-linked receptors. In contrast, curves obtained from both cortical regions from AD brains fit a single site m odel with low affinity in the presence or absence of GppNHp. On the ot her 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(1) high affinity agonist binding observed in AD is not a gl obal defect, rather it appears to be restricted to discrete regions th at are correlated with a relative abundance of neuritic/core plaques b ut not diffuse plaques or neurofibrillary tangles.