Flynn D D, Weinstein D A, Mash D C
Department of Pharmacology, University of Miami School of Medicine, FL 33136.
Ann Neurol. 1991 Mar;29(3):256-62. doi: 10.1002/ana.410290305.
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. M1 muscarinic receptors exhibited both high (KH) and low (KL) affinities for the agonist carbachol. High-affinity agonist binding to M1 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 KL/KH ratio for AD as compared to control samples. Choline acetyltransferase activities correlated significantly with the KL/KH ratios (r = 0.73, p less than 0.001). These data suggest that the KL/KH ratio for muscarinic agonists may serve as a neurochemical 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.
胆碱能替代疗法在阿尔茨海默病（AD）中几乎没有产生临床改善效果或根本没有效果。由于大脑皮层中突触后毒蕈碱受体的数量保持不变，其他神经递质系统的参与可能是导致这种疗效有限的原因。或者，在AD中，毒蕈碱受体与其核苷酸结合蛋白之间可能存在耦合缺陷，这将严重限制胆碱能激动剂激活皮质内第二信使的能力。为了探究这种可能性，我们评估了在死后额叶皮质中假定的M1毒蕈碱受体与鸟嘌呤核苷酸调节蛋白形成高亲和力激动剂 - 受体复合物的能力。通过卡巴胆碱/[3H] - 哌仑西平竞争测定M1毒蕈碱受体的激动剂亲和力状态。M1毒蕈碱受体对激动剂卡巴胆碱表现出高亲和力（KH）和低亲和力（KL）。AD患者死后额叶皮质样本中，激动剂与M1受体的高亲和力结合减少，表现为KH值增加。低亲和力激动剂结合（KL值）在AD中未发生变化，并且与在鸟嘌呤核苷酸存在下测定的未偶联受体的KL值无显著差异。与对照样本相比，AD患者KH值的增加导致平均KL/KH比值下降了70%。胆碱乙酰转移酶活性与KL/KH比值显著相关（r = 0.73，p < 0.001）。这些数据表明，毒蕈碱激动剂的KL/KH比值可能作为疾病严重程度的神经化学标志物。AD中M1受体亚型形成高亲和力激动剂状态的能力降低可能是胆碱能替代疗法未能改善记忆和认知特定特征的原因。
