| Popis: |
The potential usefulness of cholinergic replacement therapy for Alzheimer disease (AD) is dependent upon retention of postsynaptic muscarinic receptors and their transduction mechanisms long after the degeneration of cholinergic nerves. The receptors most clearly associated with cholinergic cerebral excitation are m1 muscarinic receptors, which work via a G protein to activate phospholipase C. The ability of these receptors to couple to their associated G protein was assessed in the middle temporal gyrus of postmortem brains from persons with and without AD. A low concentration of [3H]-pirenzepine (1 nM) was used to label m1 receptors preferentially. The affinity of the agonist, oxotremorine-M, for labeled receptors and the ability of these receptors to couple with G protein were assessed by competition between the agonist and 1 nM [3H]-pirenzepine in the presence and absence of guanine nucleotide. Brain tissue from 7 patients with AD and five age-matched controls showed very similar levels of labeled receptors, agonist affinities for the high- and low-affinity states of m1 receptors, and guanine nucleotide-sensitive high-affinity binding. It is concluded that the coupling of m1 receptors to G protein is adequate to permit responses to exogenous muscarinic drugs in AD. |
