Neurogenic effects of amyloid beta-proteins and gangliosides in AD

描述（由申请人提供）：在过去的十年中，在认识神经干细胞在神经发生和神经修复中的生物学潜力方面取得了重大进展。这一进展引起了利用这些多能细胞治疗各种神经退行性疾病的巨大兴趣。人们意识到，成人大脑中可能发生的神经发生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起着重要作用。特别是，越来越多的文献记录了阿尔茨海默病（AD）患者大脑中神经发生的存在。后一种观察结果表明，神经干细胞和/或神经祖细胞（NSCs/ npc）的异常可能与神经退行性疾病（如AD）的发病机制有关。因此，在疾病发展过程中神经发生的特征应该为阿尔茨海默病和相关疾病的治疗提供可能性。由于淀粉样b蛋白（ABs）和淀粉样b蛋白前体（APP）已被证明与神经节苷类相互作用，而神经节苷类已知影响神经元的存活和分化，因此这种相互作用应特别重要。我们的工作假设是，ABs和APP可能损害NSCs/ npc的神经源性潜能，从而参与AD的发病机制。由于神经节苷脂在AD的老年斑中表达，并且似乎与ABs和APP相互作用，因此它们可能被用作治疗AD的药物。为了验证这些假设，我们提出了以下具体目标来研究AD中NSCs/ npc的增殖和存活。（1）. 我们将研究ABs和APP对胚胎脑制备的NSCs/NPCs的命运（存活、增殖和分化）的影响。（2）. 我们将研究神经发生过程中神经节苷脂组成的变化，特别是在信号事件发生的小窝中。（3). 我们将研究神经节苷类药物对体外培养的NSCs/ npc命运的影响。作为短期目标，我们希望阐明抗体和抗体/神经节苷脂复合物在nec中的作用，这可能是AD致病机制的基础。我们的长期目标是开发一种神经节苷类药物来促进阿尔茨海默病的神经发生。

DESCRIPTION (provided by applicant): In the past decade, major progress has been made in recognizing the biological potential of neural stem cells in neurogenesis and neural repair. This progress has generated tremendous interest in utilizing these multipotent cells for the treatment of a variety of neurodegenerative disorders. There is an awareness that neurogenesis can occur in the adult brain that may play important roles not only in learning and memory, but also in the functional recovery from brain injuries. In particular, there is a growing body of literature documenting the presence of neurogenesis in the brain of Alzeheimer's disease (AD). This latter observation suggests that abnormalities in neural stem cells and/or neural progenitor cells (NSCs/NPCs) may contribute to the pathogenesis of neurodegenerative diseases, such as AD. Thus, characterization of neurogenesis during disease development should provide possibilities for the treatment of AD and related disorders. Since amyloid B-proteins (ABs) and amyloid B-protein precursor (APP) have been shown to interact with gangliosides that are known to affect neuronal survival and differentiation, such interaction should assume particular importance. Our working hypothesis is that ABs and APP could impair the neurogenic potential of NSCs/NPCs, which contributes to the pathogenesis of AD. Since gangliosides are expressed in senile plaques in AD and appear to interact with ABs and APP, they can potentially be exploited as therapeutic agents for the treatment of AD. To test these hypotheses, we propose the following specific aims to examine the proliferation and survival of NSCs/NPCs in AD. (1). We will examine the effects of ABs and APP on the fate (survival, proliferation and differentiation) of cultured NSCs/NPCs prepared from embryonic brains. (2). We will examine changes in ganglioside composition during neurogenesis, especially in caveolae where signaling events occur. (3). We will examine the effect of gangliosides on ABs and APP on the fate of NSCs/NPCs in vitro. As a short-term goal, we wish to clarify the role of ABs and ABs/ganglioside complexes on NECs that may underlie the pathogenic mechanisms of AD. Our long-term goal is to develop a ganglioside therapy for enhancing neurogenesis in AD.