Effects of Gangliosides on Neural Stem Cells: Role in Neuroregeneration

描述(由申请人提供)： 在过去的二十年里，人们对神经干细胞在神经发生和神经修复中的生物学潜力的认识非常令人兴奋。所取得的巨大进展引起了人们对利用多能神经干细胞进行神经修复和治疗各种神经退行性疾病的浓厚兴趣。人们意识到，神经发生可以发生在成人的大脑中，它不仅在学习和记忆中发挥重要作用，而且在脑损伤后的功能恢复中也发挥着重要作用。后一项观察还指出，神经干细胞和/或神经前体细胞(NPC)的损伤可能有助于神经退行性疾病的发病，如阿尔茨海默病(AD)。相反，在疾病发展过程中表征和促进神经发生应该为治疗阿尔茨海默病和相关疾病提供可能性。由于淀粉样蛋白2-蛋白(A2S)和淀粉样前体蛋白(APP)是AD的可能病因，已被证明与已知具有神经保护作用的神经节苷脂相互作用，这种相互作用可能具有特别重要的作用。我们的工作假设是，在一定条件下，A2S和APP可以损害NSCs/NPC的神经发生潜能，这种损害参与了AD的发病。由于神经节苷脂在AD患者的老年斑中表达，并似乎与A2和APP相互作用，因此它们可能被开发为治疗AD的药物。为了验证这一假说，我们提出了以下具体目标：(1)检测AD模型小鼠脑内神经节苷脂组成和神经发生的变化。(2)观察神经节苷脂A2和APP对神经干细胞存活、增殖和分化的影响。作为一个短期目标，我们将阐明A2和A2/神经节苷脂复合体在神经干细胞中的作用，这可能是AD发病机制的基础。S目前对其神经退行性疾病没有任何有效的治疗方法，拯救神经元的尝试也是无效的，尽管制药公司花费了巨额资金，但我们的长期目标是寻求促进AD脑内成人神经发生的策略，以实现功能恢复。

DESCRIPTION (provided by applicant): The past two decades have witnessed considerable excitement in realizing the biological potential of NSCs in neurogenesis and neural repair. The tremendous amount of progress made has generated keen interest in utilizing multipotent NSCs for neural repair and for the treatment of a variety of neurodegenerative diseases. There is an awareness that neurogenesis can occur in the adult brain and that it may play important roles not only in learning and memory, but also in functional recovery from brain injuries. This latter observation also points to the fact that impairment of NSCs and/or neural precursor cells (NPCs) may contribute to the pathogenesis of neurodegenerative diseases, such as Alzheimer's disease (AD). Conversely, characterization and promotion of neurogenesis during disease development should provide possibilities for the treatment of AD and related diseases. Sinceamyloid 2- proteins (A2s) and amyloid precursor protein (APP), possible causes of AD, have been shown to interact with gangliosides that are known to have neuroprotective effects, such an interaction could assume particular importance. Our working hypothesi is that A2s and APP, under certain conditions, could impair the neurogenic potential of NSCs/NPCs, and that impairment contributes to the pathogenesis of AD. Since gangliosides are expressed in senile plaques in AD and appear to interact with A2s and APP, they can potentially be exploited as therapeutic agents for the treatment of AD. To test this hypothesis, we propose the following specific aims: (1)To examine changes of ganglioside composition and neurogenesis in brains of AD model mice. (2)To examine the effects of pretreatment of gangliosides with A2s and APP on the fate of NSCs (survival, proliferation, and differentiation). As a short-term goal, we will clarify the role of A2s and A2/ganglioside complexes in NSCs that may underlie the pat hogenic mechanisms o f A D. S ince t here hav e not been any e ffective t herapies for t his neurodegenerative disorder and attempts to rescue neurons are ineffective despite the expenditure of an enormous amount of fund from pharmaceutical companies, our long-term goal is to seek strategies to promote adult neurogenesis in AD brain to achieve functional recovery.