簇集蛋白基于脑神经元线粒体自噬及脑功能连接的作用对晚发型阿尔茨海默病机制研究

The prediction and treatment of late-onset Alzheimer’s disease (LOAD) is a great challenge to physicians and scientists alike. Multiscale models help to improve the prediction. Directive functional connectivity is favor of building the early makers for LOAD. Research studies have studied the local brain functional network, though not focus on the full brain networks. It has been hypothesized that the competitive binding of CLU and Beclin1 with autophagy related proteins results in decreased Parkin mediated autophagy, causing mitophagy reduction, increased Aβ chain deposit as well as corresponding decline in brain functional networking and cognitive function. In view of that, this paper reviews the link among CLU, brain functional networking, cognitive function as well as Alzheimer’s disease related markers so as to further comprehend the underlying mechanism, and ultimately improve the prevention and treatment of this debilitating disease.

晚发型阿尔茨海默病（Late-onset Alzheimer’s disease, LOAD）的预测和治疗一直是神经精神学领域的难题，多因素联合可提高预测特异度。基于有向功能连接的研究有利于提取早期标记物，项目组前期已对局部网络有向功能连接展开研究，但缺乏全脑数据。簇集蛋白（Clusterin, CLU）增加发病风险，影响脑功能连接及认知。假设CLU与Beclin1竞争结合自噬相关蛋白，减弱Parkin介导的自噬，影响受损线粒体清除，导致Aβ沉积，进而损害脑功能连接及认知。因此，我们拟联合脑功能连接、CLU和认知功能，构建CLU-脑功能连接-认知多模态标记物，提高对LOAD的预测特异度，并从线粒体自噬和功能连接角度阐释CLU对LOAD的病理机制，为早期预测及挖掘潜在治疗靶点提供坚实的理论和实验依据，在临床上具有广阔前景。

晚发型阿尔茨海默病（Late-onset Alzheimer’s disease, LOAD）的预测和治疗一直是神经精神学领域的难题，多因素联合可提高预测特异度。我们发现了一个关键的有早期警示意义的脑功能网络及脑区，完善了LOAD的脑功能网络，阐释了脑网络和自噬、肠道菌群关联机制，建立了具有预测效果的多因素诊断模型。研究了脑功能影响交叉网络模式及半球网络模型在LOAD、MCI 及正常健康老年人中的差异，揭示了脑功能在参与LOAD中的早期警示意义及相关机理，阐明了脑功能、线粒体自噬及肠道菌群在LOAD发病中内在关联机制，建立完善了针对LOAD的多维度、多模式的诊断模型，为LOAD的早期诊断、挖掘潜在治疗靶点提供了提供坚实的理论和实验依据，在临床上具有广阔前景。