阿尔茨海默病中M1受体解偶联对AMPA受体介导突触可塑性与认知功能的调控机制

Alzheimer’s disease (AD) is a devastating neurodegenerative disease and the most prevalent form of dementia, causing significant socioeconomic burden. It has been widely observed that the coupling between M1 receptors and G proteins decreases significantly in the brains of AD patients. Our latest studies showed that via coupling to Gαs, M1 receptors activated cAMP-PKA signaling pathway, and then regulated the trafficking of AMPA receptor subunits GluA1 to facilitate cognitive function. However, in pathological conditions of AD, how the uncoupling between M1 receptors and G proteins regulates the trafficking of AMPA receptors and cognitive dysfunction remains unclear. To clarify the effects and mechanisms of the pathological uncoupling would provide a fundamental basis for improving cognitive function in AD by selective M1 receptors agonists, which can specifically activate the Gαs-PKA pathway. Thus, we are going to investigate the coupling status of different G protein subtypes to M1 receptors in the brains of AD animal models and the effects on the trafficking of AMPA receptors, to elucidate the whole regulation pathway involved in the regulation of AMPA receptors tracfficking via M1 receptors-Gαs coupling and the change in AD animal models, and to explore how selective activation of Gαs-PKA signaling pathway improves synaptic plasticity and cognition in AD animal models. The results will provide a new therapeutic strategy to improve the cognitive impairment in AD, through selective activation of M1 receptors-Gαs-PKA signaling.

阿尔茨海默病（AD）是以进行性认知障碍为主要特征的神经退行性疾病，给家庭和社会带来沉重负担。研究报道，AD患者脑内M1受体与G蛋白之间出现偶联程度显著下降。我们发现在正常生理状态下，通过与Gαs蛋白偶联激活cAMP-PKA通路，M1受体可调控AMPA受体GluA1运输并增强小鼠学习记忆。但AD病理条件下M1受体-G蛋白解偶联如何影响AMPA受体运输以及认知功能尚不清楚，阐明解偶联在上述过程中的作用及机制，可为利用M1受体Gαs-PKA通路选择性激活剂干预AD认知障碍提供理论依据。本课题拟研究AD病理状态下M1受体与Gα各亚型的偶联状态并考察其对AMPA受体运输的影响；探究M1受体偶联Gαs蛋白调控AMPA受体运输的通路及其在AD中的变化；探讨选择性激活Gαs-PKA通路对突触可塑性及AD认知障碍的改善作用。研究成果将为AD认知障碍提供新的干预途径。

M1型胆碱受体（M1受体）属于GPCR受体，是学习记忆功能调控最关键的亚型和AD治疗最有潜力的药物靶点之一。配体可以选择性地激活受体下游特定信号通路的现象被称为“信号偏好”（signaling bias），因信号偏好可最大限度地提高干预效应、降低副作用，具有信号偏好特性的药物开发已经成为当前M1受体研究的热点。尸检结果显示AD患者脑内M1受体与下游G蛋白之间偶联程度显著下降，存在信号转导障碍，但M1受体与不同G蛋白的偶联及其信号偏好对突触可塑性和认知功能的影响尚不十分清楚。我们前期研究证明M1受体可以通过调控AMPA受体运输增强小鼠学习记忆能力，本课题旨在进一步考察M1受体与G蛋白解偶联对其调控AMPA受体运输的影响，阐明激活M1受体调控APMA受体运输对下游信号通路的信号偏好，探究激活M1受体调控AMPA受体运输是否改善AD模型小鼠认知障碍及作用机制。研究发现激活M1受体可以改善野生型小鼠Aβ诱导的认知障碍，主要是通过增强AMPA受体GluA1亚基蛋白表达、增强Ser845位点磷酸化，促进AMPA受体运输到突触后部位实现；阐明激活M1受体正构位点调控AMPA受体运输的机制，即M1受体偶联Gαs调节cAMP-PKA通路，激活PI3K-Akt-mTOR活性从而增强Ser845位点磷酸化，促进AMPA受体运输到树突棘，增强突触可塑性；阐明激活M1受体正构、别构双位点，能够增强M1受体下游PKC、Ras分子活性从而促进AMPA受体运输。本课题研究证明激活M1受体正构位点或双位点、偏好性激活下游信号通路增强AMPA受体运输到突触后膜是改善AD模型动物认知障碍的有效方法，为调节M1受体下游偶联信号通路干预AD认知障碍提供理论依据，为实现M1受体下游信号通路选择性激活提供新思路，有助于推进AD创新药物的研发。