M1 Muscarinic Receptor Activation Rescues beta-Amyloid-Induced Cognitive Impairment through AMPA Receptor GluA1 Subunit
M1 Muscarinic Receptor Activation Rescues beta-Amyloid-Induced Cognitive Impairment through AMPA Receptor GluA1 Subunit
复制标题
M1 毒蕈碱受体激活通过 AMPA 受体 GluA1 亚基拯救 β-淀粉样蛋白诱导的认知障碍
DOI：
10.1016/j.neuroscience.2019.04.007
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发表时间：
2019
期刊：
影响因子：
3.3
通讯作者：
Qiu Yu
中科院分区：
文献类型：
--
作者：
Zhao Lan Xue;Chen Mu Wen;Qian Yue;Yang Qian Hao;Ge Yan Hui;Chen Hong Zhuan;Qiu Yu
M1毒蕈碱受体长期以来被认为是治疗阿尔茨海默病（AD）认知障碍的潜在治疗靶点。我们之前的研究表明，M1受体促进AMPA受体GluA1亚基的膜插入和突触传递。在本研究中，我们试图确定M1受体的激活是否会通过调节GluA1亚基来挽救AD模型小鼠的认知障碍。对于注射聚集性β-淀粉样蛋白（Aβ）片段导致学习记忆受损的小鼠，激活M1受体可以通过减少Morris水迷宫探针测试中寻找平台的潜伏期和在目标象限停留的时间来挽救M1受体。然而，在GluA1的Ser845残基突变为丙氨酸的小鼠中，这种效果被消除了。此外，M1受体的激活增强了a β注射野生型小鼠海马中GluA1的表达及其Ser845位点的磷酸化，并促使GluA1与突触后标记物PSD95结合，而突变小鼠则没有。此外，对于9月龄APP/PS1转基因AD模型小鼠，M1受体激活并不能明显改善认知功能障碍，这可能与晚期AD相似。此外，在海马中未观察到GluA1表达增强及其在Ser845位点的磷酸化。综上所述，该研究表明M1受体激活通过调节含有glua1的AMPA受体的转运来挽救认知缺陷，靶向M1受体的治疗方法应针对轻度AD甚至AD前期。
M1 muscarinic receptors have long been identified as a potential therapeutic target for the treatment of cognitive impairment in Alzheimer's disease (AD). Our previous study has shown that M1 receptors promote membrane insertion and synaptic delivery of AMPA receptor GluA1 subunit. In this study, we sought to determine whether activation of M1 receptor would rescue the cognitive impairment in AD model mice through modulation of GluA1 subunit. For the mice injected with aggregated β-amyloid (Aβ) fragments to impair learning and memory, activation of M1 receptors could rescue it by reducing the latency to find the platform and spending more time in the target quadrant in the probe test in the Morris water maze. However, such an effect was ablated in mice with Ser845 residue of GluA1 mutated to alanine. Furthermore, the activation of M1 receptors enhanced the expression of GluA1 and its phosphorylation at Ser845 and drove GluA1 to incorporate with PSD95, a postsynaptic marker, in the hippocampi from Aβ-injected wild type mice but not from the mutant mice. Moreover, for 9-month-old APP/PS1 transgenic AD model mice, which may resemble the late AD, M1 receptor activation could not improve the cognitive impairment significantly. In addition, the enhancement of GluA1 expression and its phosphorylation at Ser845 were not observed in their hippocampi. Taken together, the study indicated that M1 receptor activation rescued the cognitive deficit through modulating the trafficking of GluA1-containing AMPA receptors and the therapeutics targeting M1 receptors should aim at mild AD or even pre-AD.