CNS Stem Cells for neurodegenerative disease research

描述(申请人提供)：神经退行性蛋白质错误折叠疾病，其中最常见的是阿尔茨海默病(AD)，对社会造成毁灭性的个人和经济损失。中枢神经系统干细胞(CNS-SC)移植被吹捧为一种有前途的治疗阿尔茨海默病(AD)和其他退行性脑疾病的方法，无论是通过替换丢失的细胞还是作为治疗药物的载体。CNS-SC移植也可能为研究疾病过程和机制提供新的途径。这个试点项目的主要目的是评估和改进神经球移植作为剖析tau病理的发病机制和传播的工具。将探索两种模式：1)将含有神经球的CNS-SC从没有疾病的小鼠移植到疾病模型中，以及2)将神经球从疾病模型移植到没有疾病的小鼠身上。这些先导性研究的基础是针对额颞叶痴呆(FTD)的特征良好的RTG(TauP301L)4510模型。AD以细胞外Ass、淀粉样斑块和由聚集的tau蛋白组成的细胞内神经纤维早期缠结(NFTs)为特征。在这两种疾病中，NFT与认知能力下降、神经元丧失和痴呆症的关系比斑块更密切，这证明了FTD模型与AD和其他神经官能症的相关性。有证据表明，细胞外可溶形式的tau，而不是细胞内的神经纤维缠结(NFTs)，可能是神经元功能障碍和细胞死亡的触发因素。实验将比较将表达egfp的tau基因缺失的小鼠和表达tau基因的小鼠的神经球移植到表达类似水平的人突变或野生型tau的新生rtg(TauP301)和rtg(Tauwt)小鼠中，并追踪细胞存活、分化为神经元和后代形成突触的情况。 移植的细胞。除了解决细胞外tau聚集体的有害影响是否需要内源性tau表达的问题外，替换丢失的tau 将对宿主神经元进行评估。该项目将解决以下问题：来自RTG(TauP301L)神经球的神经元是否会发展为tau病，以及tau病的传播是否受到移植和宿主中tau初级结构不匹配的影响。将开发改进的方法和工具，以促进干细胞移植在了解疾病机制方面的应用；这些方法和工具将被证明是有价值的，超出了这一具体项目。

DESCRIPTION (provided by applicant): Neurodegenerative protein misfolding diseases, the most common of which is Alzheimer's disease (AD), exact devastating personal and economic tolls on society. CNS stem cell (CNS-SC) transplantation has been touted, justifiably, as a promising approach for treatment of Alzheimer's disease (AD) and other degenerative brain diseases either by replacing lost cells or as a vehicle for delivery of therapeutic agents. CNS-SC transplantation also may offer new approaches for dissecting disease processes and mechanisms. The broad aim of this pilot project is to assess and refine neurosphere transplantation as a tool to dissect pathogenic mechanisms and spread of tau pathology. Two paradigms will be explored: 1) transplantation of CNS-SC containing neurospheres from mice that do not develop disease into disease models, and 2) transplantation of neurospheres from disease models into mice that do not develop disease. The substrate for these pilot studies is the well-characterized rTg(tauP301L)4510 model for the tauopathy frontotemporal dementia (FTD). AD is characterized by extracellular Ass amyloid plaques and intracellular neurofibrillarly tangles (NFTs) composed of aggregated tau protein. Of the two, NFTs are more tightly associated with cognitive decline, neuron loss, and dementia than are plaques, arguing for the relevance of the FTD model for AD as well as other tauopathies. Evidence suggests that soluble extracellular forms of tau, rather than intracellular neurofibrillary tangles (NFTs), may be the triggers of neuronal dysfunction and cell death. Experiments will compare transplants of neurospheres from eGFP-expressing tau null and mouse tau-expressing mice into newborn rTg(tauP301) and rTg(tauwt) mice that express comparable levels of human mutant or wild type tau, and track cell survival, differentiation into neurons, and synapse formation by the progeny of the transplanted cells. In addition to addressing the question of whether endogenous tau expression is required for deleterious effects of extracellular tau aggregates, replacement of lost host neurons will be assessed. The project will address the questions of whether neurons from rTg(tauP301L) neurospheres develop tauopathy and whether spread of tauopathy is influenced by mismatching of tau primary structures in the transplant and the host. Refined methods and tools will be developed to facilitate application of stem cell transplantation to understanding disease mechanisms; these should prove valuable beyond this specific project.