Cholinergic replacement therapies have yielded little or no clinical improvement in Alzheimer's disease (AD). Since the number of postsynaptic muscarinic receptors remains unchanged in the cerebral cortex, the involvement of other neurotransmitter systems may account for this limited efficacy. Alternatively, there may be a defective coupling of the muscarinic receptor with its nucleotide-binding protein in AD, which would severely limit the ability of cholinergic agonists to activate intracortical second messengers. To address this possibility, we assessed the ability of the putative M1 muscarinic receptor to form high-affinity agonist-receptor complexes with guanine nucleotide regulatory proteins in postmortem frontal cortex. Agonist affinity states of the M1 muscarinic receptor were measured by carbachol/[3H]-pirenzepine competition. Ml muscarinic receptors exhibited both high (KH) and low (KI) affinities for the agonist carbachol. High-affinity agonist binding to Ml receptors in postmortem frontal cortex samples from subjects with AD was reduced, demonstrated by an increase in the KH value. Low-affinity agonist binding (KL value) was unchanged in AD and was not significantly different from the KL value for the uncoupled receptor determined in the presence of guanine nucleotides. The increase in the KH value resulted in a 70% decrease in the average KI/KH ratio for AD as compared to control samples. Choline acetyltransferase activities correlated significantly with the KI/KH ratios (r = 0.73, p < 0.001). These data suggest that the KL/KH ratio for muscarinic agonists may serve as a neuroehemical marker of disease severity. The reduced ability of the M1 receptor subtype to form a high-affinity agonist state in AD may account for the failure of cholinergic replacement therapies to improve specific features of memory and cognition.
ASJC Scopus subject areas
- Clinical Neurology