Yi Jee Hyun, Whitcomb Daniel J, Park Se Jin, Martinez-Perez Celia, Barbati Saviana A, Mitchell Scott J, Cho Kwangwook
Bristol Medical School, Faculty of Health Sciences, University of Bristol, Bristol BS1 3NY, UK.
Department of Life and Nanopharmaceutical Sciences, Kyung Hee East-West Pharmaceutical Research Institute, College of Pharmacy, Kyung Hee University, Seoul 130-701, Korea.
Brain Commun. 2020;2(2):fcaa058. doi: 10.1093/braincomms/fcaa058. Epub 2020 May 12.
Aggregation of amyloid beta and loss of cholinergic innervation in the brain are predominant components of Alzheimer's disease pathology and likely underlie cognitive impairment. Acetylcholinesterase inhibitors are one of the few treatment options for Alzheimer's disease, where levels of available acetylcholine are enhanced to counteract the cholinergic loss. However, these inhibitors show limited clinical efficacy. One potential explanation for this is a concomitant dysregulation of cholinergic receptors themselves as a consequence of the amyloid beta pathology. We tested this hypothesis by examining levels of M1 muscarinic acetylcholine receptors in the temporal cortex from seven Alzheimer's disease and seven non-disease age-matched control brain tissue samples (control: 85 ± 2.63 years old, moderate Alzheimer's disease: 84 ± 2.32 years old, -value = 0.721; eight female and six male patients). The samples were categorized into two groups: 'control' (Consortium to Establish a Registry for Alzheimer's Disease diagnosis of 'No Alzheimer's disease', and Braak staging pathology of I-II) and 'moderate Alzheimer's disease' (Consortium to Establish a Registry for Alzheimer's Disease diagnosis of 'possible/probable Alzheimer's disease', and Braak staging pathology of IV). We find that in comparison to age-matched controls, there is a loss of M1 muscarinic acetylcholine receptors in moderate Alzheimer's disease tissue (control: 2.17 ± 0.27 arbitrary units, = 7, Mod-AD: 0.83 ± 0.16 arbitrary units, = 7, two-tailed -test, = 4.248, = 0.00113). Using a functional rat cortical brain slice model, we find that postsynaptic muscarinic acetylcholine receptor function is dysregulated by aberrant amyloid beta-mediated activation of metabotropic glutamate receptor 5. Crucially, blocking metabotropic glutamate receptor 5 restores muscarinic acetylcholine receptor function and object recognition memory in 5XFAD transgenic mice. This indicates that the amyloid beta-mediated activation of metabotropic glutamate receptor 5 negatively regulates muscarinic acetylcholine receptor and illustrates the importance of muscarinic acetylcholine receptors as a potential disease-modifying target in the moderate pathological stages of Alzheimer's disease.
淀粉样蛋白β的聚集和大脑中胆碱能神经支配的丧失是阿尔茨海默病病理的主要组成部分，可能是认知障碍的基础。乙酰胆碱酯酶抑制剂是治疗阿尔茨海默病的少数选择之一，通过提高可用乙酰胆碱水平来抵消胆碱能缺失。然而，这些抑制剂的临床疗效有限。对此的一种潜在解释是，淀粉样蛋白β病理导致胆碱能受体本身同时出现失调。我们通过检测7个阿尔茨海默病脑组织样本和7个非疾病年龄匹配对照脑组织样本（对照：85±2.63岁，中度阿尔茨海默病：84±2.32岁，P值 = 0.721；8名女性和6名男性患者）颞叶皮质中M1毒蕈碱型乙酰胆碱受体的水平来验证这一假设。样本分为两组：“对照”（阿尔茨海默病注册协会诊断为“无阿尔茨海默病”，Braak分期病理为I-II）和“中度阿尔茨海默病”（阿尔茨海默病注册协会诊断为“可能/很可能是阿尔茨海默病”，Braak分期病理为IV）。我们发现，与年龄匹配的对照相比，中度阿尔茨海默病组织中M1毒蕈碱型乙酰胆碱受体减少（对照：2.17±0.27任意单位，n = 7，中度阿尔茨海默病：0.83±0.16任意单位，n = 7，双尾t检验，t = 4.248，P = 0.00113）。使用功能性大鼠皮质脑片模型，我们发现代谢型谷氨酸受体5的异常淀粉样蛋白β介导激活会使突触后毒蕈碱型乙酰胆碱受体功能失调。至关重要的是，阻断代谢型谷氨酸受体5可恢复5XFAD转基因小鼠的毒蕈碱型乙酰胆碱受体功能和物体识别记忆。这表明淀粉样蛋白β介导的代谢型谷氨酸受体5激活对毒蕈碱型乙酰胆碱受体产生负调节作用，并说明了毒蕈碱型乙酰胆碱受体作为阿尔茨海默病中度病理阶段潜在疾病修饰靶点的重要性。
