阿尔兹海默病（AD）是发生在老年及老年前期的一种神经退行性疾病，主要临床表现为认知功能障碍，目前尚缺乏有效的防治措施。突触可塑性被认为是学习记忆的细胞分子基础，是一个被公认的学习记忆模型。课题组前期研究发现，双特异性蛋白磷酸酶1（MKP-1）在AD病人脑组织中表达降低，而上调MKP-1表达则可以改善AD模型小鼠的突触可塑性和学习记忆。然而，MKP-1如何调控突触可塑性和学习记忆并不清楚。本项目预实验发现，MKP-1可与AMPA受体亚基GluA1相互作用，抑制突触后AMPA受体内吞。因此，我们推测：AD发病早期，MKP-1表达降低，导致其与AMPA受体相互作用减弱，突触后AMPA受体内吞增加，引起突触可塑性损伤和认知障碍。为了验证这一假设，本项目拟结合行为学、药理学和基因干预等技术，从基因、分子、细胞和整体的不同层面阐述MKP-1抑制AMPA受体内吞的分子机制，为AD防治提供新的思路和靶点。

Alzheimer’s disease (AD) is a common neurodegenerative disease that occurs in senile and presenile. The main clinical manifestation is cognitive dysfunction, and there is no effective prevention and treatment measures. Synaptic plasticity has been widely accepted as the molecular and cellular mechanism underlying learning and memory. Our previous study found that the expression of mitogen-activated protein kinase phosphatase 1 (MKP-1) was reduced in the brain of AD patients, While upregulation of MKP-1 could ameliorate the synaptic plasticity and learning and memory in the AD mice. However, it’s unclear that the mechanism by which MKP-1 regulates synaptic plasticity. Our preliminary experiments found that MKP-1could interact with AMPAR subunit GluA1 and inhibit the post-synaptic AMPA receptors endocytosis. Therefore, we supposed that the reduced interaction with the AMPAR caused by the decreased expression of MKP-1 will increase the AMPAR endocytosis, resulting in impaired synaptic plasticity, eventually leading to cognitive deficits. In order to verify this hypothesis, we will clarify the the molecular mechanism of MKP-1 inhibiting AMPA receptor endocytosis by behavior, pharmacology and gene intervention to provide new ideas and new targets for the prevetion and treatment of AD from genetic, molecular, cellular and the whole-organism levels.