NEURAL STERM CELLS TO TREAT AND MODEL ALZHEIMER DISEASE

对于包括阿尔茨海默病（AD）在内的许多神经系统疾病，目前的治疗主要是姑息性的，并且基于小分子设计。然而，研究已经开始研究使用干细胞来治疗和模拟神经退行性疾病。虽然干细胞已被认为是治疗AD的一种潜在方法，但迄今为止，这种方法尚未在动物模型中进行直接测试。因此，获得临床前证据以确定神经干细胞（NSC）移植是否可以为AD提供症状或疾病改善作用至关重要。在初步研究中，我们已经发现，小鼠神经干细胞短期移植到老年三重转基因小鼠（3xTg-AD）改善认知功能。 有趣的是，NSC不是通过分化成神经元或改变AB或tau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。这些初步研究结果表明，神经干细胞移植可能提供一个有前途的治疗方法。然而，AD表现为长期和进行性疾病。因此，确定NSC移植是否可以在延长的时间内提供益处至关重要。在这里，我们建议进行一个纵向检查的影响，神经干细胞移植对AD相关的认知功能在3xTg-AD小鼠。我们假设，神经干细胞为基础的治疗的长期有效性可以通过结合营养和疾病修饰的方法得到改善。因此，我们也将研究是否神经干细胞工程表达AB降解酶可以提供更实质性的长期利益。除了潜在的治疗用途外，干细胞作为一种新型而强大的人类疾病建模方法正在被积极研究。为了开始检查使用干细胞来模拟AD，我们因此提出从AD和对照患者成纤维细胞产生诱导多能干细胞（iPSC）。AB和tau及其各种组装和磷酸化状态的比较将确定遗传因素是否影响这些蛋白质的产生、寡聚化或降解。同样，将检查iPSC衍生的神经元响应于AB寡聚物处理的存活的分析，以确定AD iPSC衍生的神经元是否天生更易受疾病相关损伤的影响。

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 potential therapy for AD, to date this approach has not been directly tested in animal models. Consequently, it is critical to obtain pre-clinical evidence to determine whether neural stem cell (NSC) transplantation can offer symptomatic 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. Interestingly, NSCs rescue cognition 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 examination 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 substantial 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 susceptible to disease-related insults.