Analyses of the direct effects of Interleukin-4 signaling in neural stem/progenitor cells in control and Alzheimer's mice

阿尔茨海默病是老年人中最常见的痴呆症；然而，目前还没有治愈这种疾病的方法。阿尔茨海默病的特征是大脑皮层神经元和突触的慢性丧失，并以进行性的脑质量显著丧失为特征。此外，有能力产生更多神经元的神经干细胞/祖细胞停止增殖，因此无法产生更多神经元。阿尔茨海默病大脑的所有这些特性都会阻止我们的大脑在疾病条件下成功再生。阿尔茨海默病再生疗法的一个重要方面是设计新的和非传统的治疗方法。一种特殊的方法可能是动员内源性神经干/祖细胞以提高其增殖速度和分化能力。当结合旨在增加神经元存活和整合到回路中的方法时，新生神经元水平的升高可能会在一个非常不利的神经退化环境中提供再生输入。因此，了解干细胞在神经退化过程中的行为以及如何诱使它们产生更多神经元是至关重要的。在斑马鱼中，我们已经确定了一种与免疫相关的分子IL4，它可以在阿尔茨海默病的条件下促进NSPC的增殖。在这个方案中，我们将研究IL4信号在阿尔茨海默病小鼠模型中的作用，并将确定IL4是否可以在疾病条件下恢复NSPC的增殖能力。总体而言，我们的研究将是对神经科学领域的重要贡献，因为它有可能通过IL4识别神经炎性串扰信号机制，这可能会增强神经干细胞的增殖能力。我们的工作可以为神经退行性疾病的临床工作中的再生医学方法做出贡献，并有可能成为神经炎症研究的一个重要里程碑。

Alzheimer's disease is the most common form of dementia among elderly individuals; however, there is no cure for this disease yet. Alzheimer's disease is characterized by the chronic loss of neurons and synapses in the cerebral cortex, and by a significant loss of brain mass in a progressive manner. Additionally, the neural stem/progenitor cells that have the capacity to generate more neurons cease to proliferate, and therefore cannot produce more neurons. All of these properties of an Alzheimer brain prevents a successful regeneration of our brains in disease conditions. An important aspect of regenerative therapies for Alzheimer's disease is to design novel and unconventional therapeutic approaches. One particular way might be to mobilize the endogenous neural stem/progenitor cells to enhance their proliferation rate and differentiation capacity. When combined with approaches aiming to increase the survival and integration of neurons into circuitry, elevated levels of newly born neurons might provide a regenerative input in a highly unfavorable neurodegenerative environment. Therefore, it is of utmost importance to understand the behavior of stem cells during neurodegeneration, and how they can be coaxed to produce more neurons.In zebrafish, we have identified an immune-related molecules, IL4, which increases the proliferation of NSPCs in Alzheimer's disease conditions. In this proposal, we will investigate the role of IL4 signaling in an Alzheimer mouse model, and will determine whether IL4 can act to restore the proliferative capacity of NSPCs in disease conditions. In overall, our investigations will be an important contribution to the neuroscience field as it has the potential to identify a neuroinflammatory crosstalk signal mechanism through IL4, which might impose proliferative ability to neural stem cells. Our work can contribute to regenerative medicine approaches in clinical efforts towards neurodegenerative diseases, and has the potential to constitute an important milestone for neuroinflammation research.