CNS Stem Cells for Alzheimer's Disease Therapy

描述（由申请人提供）：阿尔茨海默病（AD）是一种进行性神经退行性疾病。它在老年人中很普遍，影响了大约400万美国人。阿尔茨海默氏症是一种异质性疾病，涉及许多因素，包括遗传因素。虽然β -淀粉样肽（AB）的积累与家族性和散发性阿尔茨海默病有关，但我们目前对AB的作用以及导致认知功能下降和神经元丧失的机制的理解是推测性的。过度表达AB肽的转基因小鼠系产生淀粉样斑块，并表现出与年龄相关的记忆缺陷。不幸的是，这些阿尔茨海默病的小鼠模型不会像人类那样导致进行性神经元丧失。这是否由于小鼠和人类神经元之间的物种差异，现在可以通过检查移植到这些AD小鼠模型中的人类神经细胞的命运来直接解决。鉴定、分离和扩增人类神经干细胞的能力为产生具有良好特征的细胞用于移植提供了机会。这些细胞的体内特性已经在实验性NOD-Scid异种移植小鼠系统中进行了广泛的测试。人类中枢神经干细胞的显著特征是它们能够在大脑内移植、迁移，并在表型上分化为三种主要细胞类型：神经元、星形胶质细胞和少突胶质细胞。在这里，我们建议研究人类中枢神经干细胞来源的神经细胞在重现阿尔茨海默病特征的小鼠模型中的命运，以评估神经细胞移植在阿尔茨海默病治疗中的效用。此外，我们还可以设想，这些干细胞凭借其生物学特性可以产生和替代丢失或功能失调的神经元。这项拨款的目的是测试人类神经干细胞作为治疗阿尔茨海默病的候选疗法。

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a progressive neurodegenerative disease. It is prevalent among the elderly, affecting approximately 4 million Americans. Alzheimer's is a heterogeneous disease involving a number of components, including genetics. Although the accumulation of beta-amyloid peptide (AB) has been associated with both familial and sporadic forms of Alzheimer's, our current understanding of the role of AB and the mechanisms leading to the decline of cognitive function and neuronal loss are speculative. Transgenic mouse lines that over express AB peptides develop amyloid plaques and show age-related memory deficits have been created. Unfortunately, these mouse models for AD do not result in progressive neuronal loss as seen in humans. Whether this is due to species differences between mouse and human neurons can now be addressed directly by examining the fate of human neural cells transplanted into these AD mouse models. The ability to identify, isolate and expand human neural stem cells provides the opportunity to generate well-characterized cells for transplantation. In vivo properties of these cells have been extensively tested in the experimental NOD-Scid xenogeneic transplant mouse system. The striking features of the human CNS-SC is their capacity to engraft, migrate within the brain, and phenotypically differentiate into the three major cell types, neurons, astrocytes, and oligodendrocytes. Here we propose to examine the fate of human CNS-SC derived neural cells in the mouse models that recapitulate features of AD to assess the utility of neural cell transplants in the treatment of AD. Moreover, one can envision that these stem cells by their very biological property could produce and replace lost or dysfunctional neurons. The objectives of this grant are to test human neural stern cells as candidate therapeutics for the treatment of Alzheimer's disease.