左旋丁基苯酞促进阿尔茨海默病神经再生和突触可塑性的作用及机制研究

项目名称： 左旋丁基苯酞促进阿尔茨海默病神经再生和突触可塑性的作用及机制研究

项目编号： No.81473200

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 彭英

作者单位： 中国医学科学院药物研究所

项目金额： 85万元

中文摘要： 神经元和突触的丢失被认为是引起阿尔茨海默病（AD）认知障碍的主要神经生物学基础，与认知障碍的相关性最为密切。我们前期研究发现左旋丁基苯酞（L-NBP）能改善多种AD模型的学习记忆障碍，减少神经元丢失，促进神经营养因子BDNF的释放和培养的神经干细胞（NSCs）的增殖，并上调具有神经营养和促进突起生长的αAPPs的生成，由此推测L-NBP对AD的防治可能与促进神经再生和突触可塑性有关。本项目拟采用不同月龄APP/PS1-AD转基因小鼠和体外培养的NSCs及海马神经元，从整体、细胞和分子水平，阐明L-NBP对海马神经再生（NSCs增殖、迁移、分化和新生神经元的成熟）和突触可塑性（结构可塑性和传递可塑性）的促进作用及其机制。预期研究结果将揭示L-NBP改善AD认知障碍的新分子机制。为L-NBP用于临床AD治疗奠定理论基础，为今后研发靶向促进神经再生和突触可塑性的理想AD治疗药物提供新思路。

中文关键词： 左旋丁基苯酞；阿尔茨海默病；神经再生；突触可塑性；学习记忆

英文摘要： Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive deterioration of cognitive functions, extracellular β-amyloid (Aβ) plaques and intracellular neurofibrillary tangles within neocortex and hippocampus. Adult hippocampal neurogenesis and synaptic plasticity play the important roles in learning and memory processes and their abnormal regulation may account for cognitive impairments associated with AD. L-3-n-butylphthalide (L-NBP) was extracted as a pure component from seeds of Apium graveolens Linn, Chinese celery. The previous studies have shown that L-NBP alleviated the learning and memory deficits induced by chronic cerebral hypoperfusion in rats. In A?-intracerebraventricular-infused rats, aged rats, APP/PS1double transgenic and APP/PS1/Tau triple transgenic AD mouse models, oral gavage with L-NBP significantly improved cognitive impairments, and reduced neuron loss, enhanced αAPPs release and reduced tau phosphorylation. Furthermore, in primary neurons and neuroblastoma SH-SY5Y cells, L-NBP attenuated A?-induced neuronal death. Alpha-APPs has been shown to have both neurotrophic and neuroprotective activities, and exerts proliferative effects on neural stem cells (NSCs). These results suggested that L-NBP might be a potential drug candidate for treatment of AD. Our late data showed that L-NBP promoted the release of brain-deprived neurotrophic factor (BDNF) and increased the proliferation of adult hippocampal cells in APP/PS1 transgenic mice. In the cultured NSCs, L-NBP enhanced the cell proliferation. Thus, we deduced that stimulating hippocampal neurogenesis might involve in the effect of L-NBP on AD treatment. In the present study, we will investigate the effect of L-NBP on the neurogenesis, synaptic plasticity, and related mechanisms in APP/PS1-Tg mice of 2, 10 and 18 month-old. Furthermore, we will observe the effect of L-NBP on the proliferation, differentiation, survival of NSCs. In addition, the protective effect of L-NBP on A?-induced NSCs injury and synaptic plasticity abnormality will be detected. L-NBP shows promising preclinical potential as a multi-target drug for the prevention and/or treatment of AD. Our study will further clarify the mechanism of L-NBP.

英文关键词： L-NBP;Alzheimer's disease;Neurogenesis;Synaptic plasticity;learning and memory