拉莫三嗪抑制阿尔茨海默病病理进展的作用及机制研究

项目名称： 拉莫三嗪抑制阿尔茨海默病病理进展的作用及机制研究

项目编号： No.81500915

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 张茂营

作者单位： 暨南大学

项目金额： 17.5万元

中文摘要： 阿尔茨海默病（Alzheimer’s Disease,AD）是一种常见的神经系统疾病，其病因和发病机制尚无满意阐述，治疗上也因存在许多瓶颈而无肯定有效的措施。近年来，研究发现在AD患者及动物模型脑内表现出更高的癫痫发生率或异常的脑电节律，这种异常神经网络活动与AD病理进展及认知损害密切相关。我们前期研究发现APP/PS1转基因小鼠脑内同样存在异常神经网络活动，抗癫痫药物拉莫三嗪能抑制APP/PS1小鼠脑内这种异常的神经网络活动，抑制AD小鼠的神经病理进展，改善其认知能力。然而拉莫三嗪在AD病理发展中的作用机制尚不明确。 基于前期工作基础，本项目从Aβ产生、Aβ诱导的慢性炎症反应及Tau磷酸化三个方面，利用细胞和转基因小鼠模型，研究拉莫三嗪治疗AD的作用机制，为理解AD发病机制提供新的视角，为临床AD的治疗提供有价值的理论依据及新的潜在方向。

中文关键词： 拉莫三嗪；阿尔茨海默病；神经超兴奋性；β-淀粉样蛋白；tau蛋白磷酸化

英文摘要： Alzheimer’s Disease (AD) is a common neurological disease, whose specific pathogenesis is still unclear. There are still no effective treatments to prevent, halt, or reverse Alzheimer’s disease. AD patients carry an increased risk of epileptic seizures or epileptiform activity, the same as transgenic animal models of the disease. This network dysfunction is closely related to cognitive deficits and the pathogenesis of AD. Network dysfunction have also been observed in APP/PS1 mice in our previously study. We have found that the chronic lamotrigine treatment suppresses abnormal spike activity, attenuates the progress of neuropathogenesis, and therefore rescues the cognitive deficits in APP/PS1 mice. However, the function and the mechanisms of lamotrigine in the pathogenesis of AD are still unclear. Therefore, this project is proposed to investigate the function and the mechanisms of lamotrigine in generation of Aβ, Aβ-induced neuroinflammation and tau pathology. The study will provide a nove perspective of the pathogenesis of AD, a potential new direction for AD treatment, and aslo valuable data for target validation of AD.

英文关键词： Lamotrigine;Alzheimer's disease;Hyperactivity;β-mayloid;Tau