iNSCs移植治疗AD小鼠脑神经修复的多维评估及机制研究

Alzheimer’s Disease(AD) causes the damage and loss of the neurons widely in the patients’ brains. Induced neural stem cells (iNSCs) (a rich source of non-tumorigenic, non-immune rejection, no ethical restrictions, representation of the process of neural development) reprogrammed from somatic cells of mice by transcription factors can recovery disfunction of brain.Now the study on iNSCs treatment of AD has not been reported, and it is still unclear how iNSCs intergrate with the host brain never system. Based on literatures, we will transplant iNSCs with autologous transplantation characteristics into AD mice at different ages. We will assess and analyze its role in the recovery of the nerve structure and function, the link of nerve fiber bundles,by multidimensional evaluation methods, including optogenetics combined with electrophysiology, non-invasive functional imaging in vivo, molecular biology, behavioral test, and single cell sequencing and weighted gene co-expression network analysis(WGCNA) to reveal association of gene networks with neural networks. This study will provide basis for iNSCs treatment of AD clinically.

阿尔茨海默病（Alzheimer’s Disease, AD）患者脑内神经元广泛受损、丢失，导致脑功能不可逆性损害。转录因子诱导的体细胞来源的诱导型神经干细胞（iNSCs）因其具有丰富来源、无致瘤性、无免疫排斥、无伦理限制、能重演神经发育过程的优势，故可实现受损脑功能修复。目前，国内外未见iNSCs治疗AD的报道，而且对于iNSCs在脑内分化后如何与宿主脑神经进行结构和功能的整合尚不清楚。基于此，本项目将小鼠体细胞转化为具有自体移植特征的iNSCs，并移植入AD小鼠的海马区，应用光遗传学结合电生理学、功能影像学、分子生物学和行为学，并联合单细胞测序、加权基因共表达网络分析等多维评价方法分析iNSCs移植入AD小鼠后神经结构和功能、神经纤维束连接等方面的修复情况，并揭示iNSCs移植后AD小鼠基因网络与神经网络的关联，旨在为将来iNSCs治疗AD的临床应用提供实验依据。

阿尔茨海默病（Alzheimer’s Disease, AD）是一种脑内神经元广泛受损、丢失的神经退行性病变，导致脑功能不可逆性损害。研究表明AD主要与脑内丢失胆碱能神经元有关。目前，国内外未见iNSCs治疗AD、及将iNSCs诱导转化为胆碱能神经元样细胞（cholinergic neuron-like cells,CNLs）及这两种细胞移植治疗AD的效果比较。我们采用单转录因子Sox2联合小分子物质将小鼠成纤维细胞诱导转化为诱导型神经干细胞（iNSCs）。利用RA联合NGF明显提高体外将iNSCs诱导分化为CNLs的效率。并将两种细胞移植入AD小鼠的海马区，应用光遗传学结合电生理学、功能影像学、分子生物学和行为学等多维评价方法分析iNSCs及CNLs移植入AD小鼠后神经结构和功能、神经纤维束连接等方面的修复情况及治疗效率的比较。