Characterization of a Potent Neurogenic Compound

描述（由申请人提供）：虽然神经发生主要发生在发育过程中，但它是一个持续终生的主动过程，并可能在正常学习和记忆中发挥作用。神经发生水平的降低随着年龄的增长而发生，并且可能发生在神经退行性疾病如阿尔茨海默病（AD）中。因此，了解中枢神经系统（CNS）内干细胞分裂和分化的分子基础值得深入研究。一种新的药物发现范例被用于选择用于治疗神经退行性疾病的候选药物，其基于在多种年龄相关病理的细胞培养模型中的功效。该方案已经确定了一种有效的口服活性化合物J147，其促进正常啮齿动物的记忆，防止AD转基因小鼠的行为缺陷和突触蛋白丢失，并逆转老年转基因AD小鼠的认知丧失。J147在小鼠、培养的成年大鼠海马前体细胞和人ESC衍生的神经前体细胞中也是神经原性的。此外，它具有抑制注定成为星形胶质细胞的细胞分裂的独特能力。本研究的总体目标是确定小鼠大脑中对J147反应的细胞的类型和命运，并使用这种化合物更好地了解体内和细胞培养模型中神经发生所涉及的分子途径。因此，对J147产生反应的神经样细胞的表型将在动物和可以产生神经或神经胶质的大鼠海马前体细胞系中表征。由于化合物如J147在AD中的治疗潜力，将询问J147是否可以在非常老的小鼠中诱导神经发生，而其他神经原性化合物不能起作用。重要的是，神经发生将通过两种独立的方法减少，并将询问J147是否仍然能够增强记忆。最后，一种新的蛋白质组学方法将被用来确定负责J147诱导的细胞分裂和神经分化的分子信号通路。这项研究的结果可能导致J147的治疗应用，其基础是操纵神经干细胞以改善CNS健康。

DESCRIPTION (provided by applicant): Although neurogenesis occurs primarily during development, it is an active process that persists throughout life, and may play a role in normal learning and memory. Decreased levels of neurogenesis occur with age and perhaps in neurodegenerative conditions such as Alzheimer's disease (AD). Therefore, understanding the molecular basis of stem cell division and differentiation within the central nervous system (CNS) deserves thorough investigation. A novel drug discovery paradigm was used to select drug candidates for the treatment of neurodegenerative diseases that is based on efficacy in cell culture models of multiple, age-associated pathologies. This scheme has identified a potent, orally active compound, J147, which facilitates memory in normal rodents, prevents behavioral deficits and synaptic protein loss in AD transgenic mice, and reverses cognitive loss in aged transgenic AD mice. J147 is also neurogenic in mice, in adult rat hippocampal precursor cells in culture, and for human ESC-derived neural precursor cells. In addition, it has the unique ability of inhibiting the division of cells destined to be astrocytes. The overall aim in this study is to identify the type and fate of cells that respond to J147 in the mouse brain and to use this compound to better understand the molecular pathways involved in neurogenesis both in vivo and in cell culture models. Therefore the phenotype of the nerve-like cells made in response to J147 will be characterized both in animals and in a rat hippocampal precursor cell line that can produce either nerve or glia. Because the therapeutic potential of compounds like J147 in AD, it will be asked if J147 can induce neurogenesis in very old mice where other neurogenic compounds fail to act. Importantly, neurogenesis will be reduced by two independent methods and it will be asked if J147 is still able to enhance memory. Finally, a new proteomics approach will be used to identify the molecular signaling pathways responsible for J147-induced cell division and nerve differentiation. Results from this study may lead to a therapeutic application of J147 based upon manipulating neural stem cells to improve CNS health.