Muscarinic acetylcholine receptor expression in memory circuits: Implications for treatment of Alzheimer disease
Muscarinic acetylcholine receptor expression in memory circuits: Implications for treatment of Alzheimer disease
复制标题
DOI：
10.1073/pnas.93.24.13541
复制
发表时间：
1996-11-26
影响因子：
11.1
通讯作者：
Levey, AI
中科院分区：
文献类型：
--
作者：
Levey, AI
毒碱乙酰胆碱受体（mAChR）的胆碱能传递与学习和记忆等高级脑功能有关，突触丧失可能导致阿尔茨海默病的症状。一个由五种遗传上不同的mAChR亚型组成的异质家族差异调节多种细胞内信号系统以及参与疾病病理的关键分子的加工。尽管在记忆回路中已经发现了许多毒蕈碱效应，包括海马中多种突触前和突触后的作用，但负责任何给定功能的分子亚型的身份仍然难以捉摸，所有5种mAChR基因都在海马中表达，亚型特异性抗体已经能够识别、定量和定位编码蛋白。m1， m2和m4 mAChR蛋白在前脑区域最丰富，它们具有不同的细胞和亚细胞定位，提示胆碱能回路中的各种突触前和突触后功能。这些亚型在阿尔茨海默病病例的死后脑样本中也有差异改变。进一步了解阿尔茨海默病中失效突触的分子药理学，以及新的亚型选择性药物的开发，可能为该疾病提供更特异性和更有效的治疗方法。
Cholinergic transmission at muscarinic acetylcholine receptors (mAChR) has been implicated in higher brain functions such as learning and memory, and loss of synapses may contribute to the symptoms of Alzheimer disease, A heterogeneous family of five genetically distinct mAChR subtypes differentially modulate a variety of intracellular signaling systems as well as the processing of key molecules involved in the pathology of the disease. Although many muscarinic effects have been identified in memory circuits, including a diversity of pre- and post-synaptic actions in hippocampus, the identities of the molecular subtypes responsible for any given function remain elusive, All five mAChR genes are expressed in hippocampus, and subtype-specific antibodies have enabled identification, quantification, and localization of the encoded proteins. The m1, m2, and m4 mAChR proteins are most abundant in forebrain regions and they have distinct cellular and subcellular localizations suggestive of various pre- and postsynaptic functions in cholinergic circuits, The subtypes are also differentially altered in postmortem brain samples from Alzheimer disease cases. Further understanding of the molecular pharmacology of failing synapses in Alzheimer disease, together with the development of new subtype-selective drugs, may provide more specific and effective treatments for the disease.