阿尔茨海默病(AD)是老龄化社会的严峻挑战，大多数AD是外环境危害因素与机体老化、遗传等内环境风险因子交互协同所致。项目组前期研究表明，环境噪声作为独立风险因素可引发海马、皮层tau蛋白异常磷酸化、β淀粉样蛋白蓄积及神经炎性反应等AD样病变，我们据此推测“环境噪声可能与典型内环境风险因子协同促进AD发生发展，是AD的重要环境病因学因素”。本项目拟应用AD模型动物，研究噪声与老龄化、ApoE4、APP/ PS1等典型内环境AD风险因子联合暴露对AD促发效应的规律特点及剂量效应关系，确定与噪声具有明确协同促发AD作用的内环境风险因素；基于iTRAQ技术解析介导噪声促发AD样变的主要已知(CRFR、NMDAR)和未知信号通路，筛选其中关键调控靶点，并应用靶点分子干预技术，最终确证其在噪声协同内环境风险因素促发AD中的作用。本研究将为AD的环境病因学提供系统实验证据，为AD防治提供新靶点和启示。

Complex interactions between the genetic background and various environmental factors underlie most Alzheimer's disease(AD), which is a great challenge to the coming aging society. Our previous study has demonstrated, for the first time, that long-term exposure to noise triggers significant and persistent hyperphosphorylation of tau and formation of pathological neurofibrillary tangles (NFT)and abnormal changes in levels of precursor protein of β-amyloid (Aβ) and inflammatory cytokines in the hippocampus and the prefrontal cortex. We therefore hypothesize that environmental noise exposure is an important factor of the etiology of AD, which may have a synergetic effect with genetic risk factors of AD. In this study,the AD animal models will be taken as research objects to investigate synergetic effect of noise exposure and risk factors of internal environment(aging or ApoE4 or APP/ PS1) on the developoment of AD and the exposure-response relationship between them in the hippocampus and the prefrontal cortex. Based on the experimental confirmation,we will determine the risk factors of internal enviroment which have synergistic effect with noise on AD. Moreover, based on the iTRAQ analysis,the signaling pathways mediating noise-induced AD pathology will be demonstrated,and the key molecular targets in regulating this peocess will be also screened and further confirmed by intervention experiment. This research will provide sufficient experimental evidence for the study of the enviromental pathogenesis of AD, and give new targets and clues to the prevention of AD.