FNDC5在认知训练改善增龄所致认知功能减退中的作用及机制研究

Age-related cognitive decline is a common serious health issue in the eldly. Cognitive training has been proven to be beneficial for age-related cognitive decline, however, the underling mechanism is unclear. . We found that the plasma concentration of irisin, a cleaved and secreted fragment of FNDC5, was significantly increased by cognitive training in human and environmental enrichment in mice. In addition, FNDC5 expression level in the dentate gyrus was also up-regulated by environmental enrichment. These results indicate that FNDC5 might mediate the effetcs of cognitive training in age-related cognitive decline.. Based on these preminary results, we will identify the role of FNDC5 in the effetcs of cognitive training in age-related cognitive decline through both gain-of-function and loss-of-function experiments in aged mice, human embryonic stem cell-derived neural precursor cells and ex-vivo mouse hippocampal slices. Besides that, with gene arrays, bioinformatic analysis, fluorescence quantitative PCR, western blotting, and imitated or reversed experiments both in vivo and in vitro, we will clarify the downstream targets responsible for the role of FNDC5 in the effects of cognitive training in age-related cognitive decline.. This project will uncover the role of FNDC5 in mediating the effetcs of cognitive training in age-related cognitive decline and also provide a new therapeutic approach for age-related cognitive decline.

增龄所致的认知功能减退是老年人群常见的健康问题，研究发现认知训练可以改善增龄所致的认知功能减退，但是其分子机制尚不清楚。我们发现认知训练组的健康老龄人血浆中鸢尾素（FNDC5的剪切分泌体）浓度显著高于对照组；丰富环境饲养的老龄小鼠认知功能改善，血浆鸢尾素浓度和海马齿状回FNDC5表达量均高于对照组，提示FNDC5可能介导了认知训练改善增龄所致的认知功能减退。本课题拟在动物整体水平、人胚胎干细胞来源的神经前体细胞和离体小鼠海马脑片上进行FNDC5功能获得性和缺失性实验，明确FNDC5与认知训练改善增龄所致的认知功能减退的关系，并借助基因芯片、生物信息学分析、荧光定量PCR、免疫印迹法以及体内、体外的模拟或逆转实验，揭示FNDC5介导认知训练改善增龄所致的认知功能减退的下游分子基础。本课题将明确认知训练改善增龄所致的认知功能减退的FNDC5机制，并开发出一个新的治疗增龄所致的认知功能减退的方法

增龄所致的认知功能减退是老年人群常见的健康问题，研究发现认知训练可以改善增龄所致的认知功能减退，其可能与FNDC5相关。本项目基于小鼠胚胎干细胞（mESCs）体外定向诱导神经元分化的系统，检测发现FNDC5的表达水平在神经元发生的过程中逐渐上升。同时，我们发现FNDC5的缺失会阻碍神经前体细胞的形成，并严重阻碍上胚层细胞分化到神经外胚层的过程。进一步机制研究发现，FNDC5极有可能是在神经诱导阶段抑制TGFβ信号通路从而保证神经诱导的正常进行的。本项目系统地研究了FNDC5在神经元发生过程中的重要作用以及其影响神经元发生的具体调控机制。