长期噪声暴露与典型内环境风险因子协同对AD的促发效应及其启动机制研究

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.

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。

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。前期研究表明，环境噪声作为独立风险因素可引发海马、皮层脑区AD样病变。本项目应用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，确定与噪声具有明确协同促发AD作用的内环境风险因素；筛选噪声促发AD样变的关键调控靶点，以阐明其在噪声协同内环境风险因素促发AD中的作用。重要研究结果包括：1) 长期噪声与增龄性因素、ApoE4、APP/ PS1等典型内环境AD风险因子联合暴露可对神经认知、病理蛋白蓄积、神经炎性反应产生异常影响，进而促发AD的发生发展；2) 长期噪声暴露后SAMP8小鼠海马脑区Wnt通路激活，进而通过调控GSK-3β，引发tau蛋白异常磷酸化，初步明确了Wnt信号通路参与了噪声与衰老因素协同暴露所致AD 特征性病理改变的过程；3) 长期噪声与ApoE4基因联合暴露后Wistar大鼠海马脑区AKT和Calpain-CDK5信号通路激活，初步明确了AKT和Calpain-CDK5信号通路激活参与了噪声与ApoE4基因协同暴露所致AD 特征性病理改变；4) 长期噪声与APP/PS1基因联合暴露使海马VDAC1与Bak蛋白表达增加，进一步促进Cyt C 释放，导致Caspase-3增加，明确了海马VDAC1-AKT-GSK3β-VDAC1正反馈信号通路在内外环境因素协调促发AD样异常神经病理改变过程中发挥重要作用。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。研究结果以论著形式在本专业高水平期刊发表论文6篇（本基金项目均为第一标注），总影响因子26。结合本单位承担的研究生教育及学科建设，培养硕士研究生共4 名，青年科技骨干1 名。完成（部分超额完成）项目规定全部指标。