Neurogenic effects of amyloid beta-proteins & gangliosides in Alzheimer's Disease

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。这一进展产生了巨大的兴趣，利用这些多能细胞治疗各种神经退行性疾病。人们意识到，神经发生可以发生在成年人的大脑中，不仅在学习和记忆中发挥重要作用，而且在脑损伤的功能恢复中也发挥重要作用。特别是，有越来越多的文献记载了阿尔茨海默病（AD）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（NSC/NPC）的异常可能有助于神经退行性疾病，如AD的发病机制。因此，表征疾病发展过程中的神经发生应提供治疗AD和相关疾病的可能性。由于淀粉样蛋白B-蛋白（AB）和淀粉样蛋白B-蛋白前体（APP）已被证明与神经节苷脂，已知影响神经元的存活和分化，这种相互作用应承担特别重要。我们的工作假设是，ABs和APP可以损害神经干细胞/NPC的神经原性潜力，这有助于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AB和APP相互作用，因此它们可以潜在地被开发为用于治疗AD的治疗剂。为了验证这些假设，我们提出了以下具体目标，以检查AD中NSC/NPCs的增殖和存活。（一）.我们将研究ABs和APP对胚胎脑制备的培养NSC/NPCs的命运（存活、增殖和分化）的影响。（二）、我们将研究神经发生过程中神经节苷脂成分的变化，特别是在信号事件发生的小窝。（三）、我们将研究神经节苷脂对AB和APP对体外NSC/NPCs命运的影响。作为一个短期目标，我们希望澄清的作用，ABs和ABs/神经节苷脂复合物的NEC，可能是AD的致病机制。我们的长期目标是开发一种神经节苷脂治疗增强AD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.