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。迄今还没有一种有效的方法能防治此病，究其主要原因是AD发病的神经机理还远没阐明。先前报道表明MAPK的活化可以加速AD的发生发展，而MKP-1可以抑制MAPK活性。然而，通过MKP-1调控MAPK活性是否参与，以及如何参与AD发病并不清楚。因此，本项目拟通过调控MKP-1探索MKP-1-MAPK信号通路在AD发病过程中的作用及相关机制。拟在AD转基因小鼠和AD细胞模型上，通过基因调控或基因敲除MKP-1，然后采用行为学方法研究其对AD小鼠认知功能的影响；电生理方法研究海马突触可塑性及相关受体功能变化；生化和免疫组化方法分析MKP-1、MAPK及AD相关病理变化。从分子、细胞和整体等不同层面阐述MKP-1在AD发病中的作用及相关分子机制，从而为防治AD的临床新型药物研发提供一条新的思路和新的靶点。

Alzheimer’s disease (AD) is a complex neurodegenerative disorders in the elderly, characterized by progressive memory loss and other cognitive dysfunctions. Nevertheless, no cure has been found for AD, mainly because of the lack of understanding of its neuropathological mechanisms. Previous reports have shown that activation of mitogen-activated protein kinase (MAPK) accelerates the development and progression of AD, and mitogen-activated protein kinase phosphatase 1 (MKP-1) is able to inhibit MAPK activity. However, it is not clear whether and how the inhibition of MAPK activation by MKP-1 is involved in the pathogenesis of AD. This project, therefore, intends to explore the role of MKP-1-MAPK signaling pathway in the pathogenesis of AD and its related mechanisms. We will utilize the transgenic mice model of AD and AD cell line to study the formation of long-term memory using the Morris water maze tests, to characterize the alteration in hippocampal synaptic plasticity and receptor functions using electrophysiological recordings, and to examine the expression of MKP-1, MAPK and AD-related pathology changes using biochemical and immunohistological assays, after genetic modulation or knock-out MKP-1. Knowledges gained from the prsent study may thus provide novel approaches and new target for the prevention and treatment of AD in clinical settings by deepening our understanding of the molecular mechanism underlying AD at molecular, cellular and whole-organism levels.