Reelin在阿尔茨海默病小鼠发病中的作用

doi:10.16098/j.issn.0529-1356.2016.06.001

摘要/Abstract

摘要：

目的探讨阿尔茨海默病（AD）小鼠病理改变、Reelin和Notch1的表达变化及DNA甲基化状态的改变，为深入了解阿尔茨海默病的发病机制提供理论依据。方法以淀粉样蛋白前体（APP）/早老素-1（PS1）双转基因小鼠为AD模型、同窝野生型小鼠为对照组，两组小鼠共计184只，利用高尔基染色、透射电子显微镜、免疫荧光染色、免疫印迹等技术检测AD模型鼠病理改变、Reelin和Notch1的表达变化及DNA甲基化状态的改变。结果 AD小鼠在约6个月时开始出现淀粉样斑沉积、神经元纤维出现缠结等病理改变；AD小鼠发病后，星形胶质细胞和小胶质细胞在淀粉样斑周围聚集增多，随病情加重逐渐增加；Reelin在淀粉样斑周围聚积形成斑块，随病情加重逐渐增多；全长Notch1受体和其活性Notch细胞内片段（NICD）在AD鼠脑部表达减少；AD小鼠脑部甲基化状态减弱，淀粉样斑中有DNA片段，但甲基化状态消失，DNA甲基转移酶1（Dnmt1）和Dnmt3a在AD小鼠中表达减少。结论 AD小鼠脑内淀粉样斑沉积，促使胶质细胞聚集、Reelin聚积形成斑块、Notch1受体表达下降及甲基化状态减弱，进一步加剧AD神经功能紊乱。

关键词: 阿尔茨海默病, 淀粉样斑, DNA甲基化, Notch1 受体, Reelin, 淀粉蛋白前体/早老素1双转基因小鼠

Abstract:

Objective To investigate the role of DNA methylation, Reelin and Notch pathways in the pathogenesis of Alzheimer’s disease(AD). Methods A total of 184 wild-type (WT) and AD mice were used for Golgi staining, immunofluorescent labeling, Western blotting and transmission electron microscopy in this study. Results The pathological changes occurred after postnatal 6 months (P6M) in the hippocampus and neocortex of AD mice, such as amyloid plaques and neurofibrillary tangles. Astrocytes and microglia usually were clustered around amyloid plaques in AD mice. With age increasing, Reelin accumulated around amyloid plaques and formed amyloid-like deposits. In AD mice, the expression of Notch1 receptor with both full-length Notch1 and Notch intracellular domain(NICD) decreased. DNA methylation decreased in AD hippocampus and neocortex; especially in amyloid plaques, the DNA methylation almost disappeared. For instance, the expression of Dnmt3a and Dnmt1 were decreased in AD mice. Conclusion The amyloid plaques in AD mice can induce the cluster of astrocytes and microglia and the accumulation of Reelin. The abnormal expressions of Notch1 receptor and DNA methyltransferase probably are the causes of the neural dysfunction in AD.

Key words: Alzheimer’s disease, Amyloid plaque, DNA methylation, Notch1 receptor, Reelin, Amyloid procursor protein/presenilin-1 double transgenic mouse

鄢明超赵培文曹晶晶王小青王倩孙仪征程艳红邓锦波. Reelin在阿尔茨海默病小鼠发病中的作用[J]. 解剖学报, 2016, 47(6): 721-730.

YAN Ming-chao ZHAO Pei-wen CAO Jing-jing WANG Xiao-qing WANG Qian SUN Yi-zheng CHENG Yan-hong DENG Jin-bo. Role of Reelin signaling pathway in the pathogenesis of Alzheimer’s disease model mice[J]. Acta Anatomica Sinica, 2016, 47(6): 721-730.

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