基于多模态磁共振成像研究APOEε4和CLU交互作用对健康人海马的调控机制

Alzheimer’s disease (AD) is an aging-related progressive neurodegenerative disease with complex genetic characteristics. The hippocampus, underlying the early pathophysiological mechanism, was modulated by Apolipoprotein E (APOE) ε4 and Clusterin (CLU) by the regulation of lipid metabolism. The interaction between APOE ε4 and CLU affected the hippocampal functional activity, and imaging genetics study found that the anterior hippocampal function was specifically regulated by CLU, while our previous study showed altered functional connectivity based on the anterior part of hippocampus was sensitive to the early effects of APOE ε4. The contrary patterns between CLU and APOEε4 indicated their different mechanisms on hippocampus-subregion, and moreover, the interaction of them on subregion was still uncertain now. Considering that the early genetic effect was influenced by development and aging, this study is thus to concentrate on hippocampus and its subregions to explore the effects of CLU and APOEε4 in large-age-scale groups. Elucidating the interaction of CLU and APOEε4 would be contributed to reveal the lipid metabolism pathway of AD neurodegenerative mechanism in ultra-early stage, as well as to discover the evolution of interacted effects with development or aging to acquire a new sensitive and specific imaging biomarker.

阿尔茨海默病（Alzhermer's disease, AD）是与衰老相关具有复杂遗传特征的神经退行性疾病。海马是探究其早期病理生理改变机制的重要靶点，其中参与脂质代谢调控基因载脂蛋白E（Apolipoprotein E，APOE）ε4和聚集素（Clusterin，CLU）对海马具有特殊调控，二者相互作用影响海马功能；遗传影像学研究发现海马前部和CLU紧密相关，而申请人前期研究发现海马后部受APOE ε4早期调控，提示APOEε4和CLU对海马内部亚区调节机制不同，而二者相互作用下海马亚区改变模式尚不清楚。由于基因早期效应受发育、老化等因素影响，本研究认为：基于海马及其亚区探究大尺度年龄变化下CLU和APOEε4对人脑的影响，有助于阐述CLU和APOEε4相互作用及其诱导下脂质代谢通路在AD病理过程中作用机制，揭示二者基因效应随发育或老化的演变规律，寻找AD敏感、特异的影像学指标。

项目组对青年、中年和老年健康人群进行了AD高危基因遗传学分析，并从功能、结构等各个尺度研究了参与脂质代谢调控基因载脂蛋白E(Apolipoprotein E，APOE)ε4、聚集素(Clusterin，CLU)等多种高危基因对健康人海马后部及全脑网络调控模式,。基于横断面及纵向研究发现，APOE ε4参与CLU等其他高危基因的调控，正常人脑老化过程主要体现为注意力、控制力的下降，并受默认网络（default mode network, DMN）、背侧注意网络（dorsal attention network, DAN）和突显网络（salience network, SAN）及皮质下网络等多种静息态功能网络调控。APOE ε4携带者虽然认知行为学表现未表现出异常，但脑网络静态和动态功能连接改变模式显著不同。海马内部前后功能连接协同海马与外侧颞叶功能活动在APOE ε4携带者随着老化过程动态增强，而基于海马后部-DMN网络连接增强可能是APOE ε4携带者在脑老化认知过程中SAN-DMN网络间功能连接失衡的的一种弥补代偿机制；DAN对APOE ε4非携带者更为敏感。初步基于脑肠轴分析研究发现肠道菌群失调(Roseburia)通过炎症因子肿瘤坏死因子-α来间接调节以杏仁核为基础的脑功能连接(左侧杏仁核-右侧顶叶下叶)。这些结果为分析AD疾病诊断的遗传影像超早期生物标注物，以及其神经炎症、脂质代谢异常为主导的多系统交互病理机制的探索提供了方法和理论依据。本项目形成了健康人群大样本多模态遗传神经影像学队列，获得被试完整的多模态磁共振(fMRI、3DT1、DTI)数据、血液标本并完成AD相关高危基因SNP位点分析和认知行为学量表等数据；为进一步研究打下良好基础。项目组目前共发表SCI论著2篇，辅助资助培养该研究方向博士研究生2名。