NEURAL STERM CELLS TO TREAT AND MODEL ALZHEIMER DISEASE

对于包括阿尔茨海默病(AD)在内的许多神经疾病，目前的治疗主要是姑息治疗，并基于小分子设计。然而，研究已经开始检查使用干细胞来治疗和模拟神经退行性疾病。尽管干细胞已被建议作为治疗AD的潜在疗法，但到目前为止，这种方法还没有在动物模型中进行直接测试。顺从，就是这样 对于获得临床前证据以确定神经干细胞(NSC)移植是否能为AD提供症状或疾病改善效果至关重要。在初步研究中，我们发现将小鼠神经干细胞短期移植到老年三重转基因小鼠(3xTg-AD)中可以改善认知功能。 有趣的是，神经干细胞并不是通过分化为神经元或改变AB或tau的水平来拯救认知，而是通过增加脑源性神经营养因子的水平和增强内源性海马突触连接来拯救认知。这些初步发现表明，神经干细胞移植可能提供一种有前途的治疗方法。然而，AD表现为一种长期的、进行性的疾病。因此，确定神经干细胞移植是否能在较长时间内提供益处是至关重要的。在这里，我们建议 目的：纵向观察神经干细胞移植对3xTg-AD小鼠AD相关认知功能的影响。我们假设，基于NSC的治疗的长期有效性可以通过结合营养和改善疾病的方法来改善。因此，我们还将研究设计成表达AB降解酶的NSCs是否可以提供更多实质性的长期好处。除了它们潜在的治疗用途外，干细胞作为一种新的和强大的人类疾病模型方法正在被积极研究。因此，为了开始研究使用干细胞建立AD模型，我们建议从AD和对照患者成纤维细胞中产生诱导多能干细胞(IPSCs)，比较AB和tau及其各种组装和磷酸化状态将确定遗传因素是否影响这些蛋白质的生产、寡聚或降解。同样，对IPSC来源的神经元对AB寡聚体治疗的反应进行生存分析，以确定AD IPSC来源的神经元是否天生更容易受到与疾病相关的侮辱。

For many neurological disorders including Alzheimer Disease (AD), current therapies are largely palliative and based on small molecule designs. However, studies have begun to examine the use of stem cells to both treat and model neurodegenerative disease. Although stem cells have been suggested as a potenfial therapy for AD, to date this approach has not been directly tested in animal models. Consequenfiy, it is critical to obtain pre-clinical evidence to determine whether neural stem cell (NSC) transplantation can offer symptomafic or disease-modifying effects for AD. In preliminary studies, we have found that short-term transplantation of murine NSCs into aged triple transgenic mice (3xTg-AD) improves cognitive function. Interesfingly, NSCs rescue cognifion not by differentiating into neurons or altering levels of AB or tau, but rather by increasing levels of brain-derived neurotrophic factor and enhancing endogenous hippocampal synaptic connectivity. These initial findings suggest that NSC transplantation may provide a promising therapeutic approach. However, AD manifests as a long-term and progressive illness. Thus, it is critical to determine whether NSC transplantation can provide benefits across an extended duration. Here we propose to perform a longitudinal examinafion of the effect of NSC transplantation on AD-related cognitive function in 3xTg-AD mice. We hypothesize that the long-term effectiveness of NSC-based therapies can be improved upon by combining both trophic and disease-modifying approaches. Thus, we will also examine whether NSCs engineered to express an AB-degrading enzyme can provide more substanfial long-term benefit. In addition to their potential therapeutic use, stem cells are being actively studied as a novel and powerful approach to model human disease. To begin to examine the use of stem cells to model AD we therefore propose to generate induced pluripotent stem cells (iPSCs) from AD and control patient fibroblasts Comparisons of AB and tau and their various assembly and phosphorylation states will determine whether genetic factors influence the production, oligomerization, or degradation of these proteins. Likewise analysis of the survival of iPSC-derived neurons in response to AB oligomer treatment will be examined to determine whether AD iPSC-derived neurons are innately more suscepfible to disease-related insults.