APP/PS1转基因鼠脑内小泛素化修饰物-1上调可能参与阿尔茨海默病老年斑形成和神经突起变性的调节
赵晓燕, 王丹丹, 单烨, 朱粹青*
复旦大学上海医学院神经生物学国家重点实验室,上海 200032
摘要
小泛素化修饰物(small ubiquitin-related modifier, SUMO)是一类重要的类泛素蛋白,研究显示一些神经退行性疾病相关蛋白可以被SUMO化修饰。本文旨在观察APP/PS1转基因阿尔茨海默病(Alzheimer’s disease, AD)鼠中SUMO-1表达及修饰的变化,并探讨SUMO-1与AD病理的关系。采用免疫印迹的方法检测12月龄的APP/PS1转基因AD鼠脑内SUMO-1表达及修饰的变化,同时用免疫共沉淀及免疫荧光的方法研究AD鼠脑内SUMO-1与tau、APP和Aβ的关系。结果显示:(1)与正常野生型小鼠相比,AD鼠脑内SUMO-1表达及其修饰的蛋白增加,同时伴有泛素化蛋白的增加;(2) AD鼠大脑皮层的RIPA可溶蛋白组份中,SUMO-1修饰的tau增加,而AT8抗体识别的磷酸化tau的SUMO-1修饰减少,但422位点磷酸化tau的SUMO-1修饰没有明显改变;(3) SUMO-1与磷酸化tau、APP及Aβ免疫荧光双标显示,在AD鼠脑内SUMO-1可在老年斑的中部和周围分布,并且 SUMO-1与AT8识别的磷酸化tau在老年斑周围的变性神经突起中有相对较多的共存,但与APP、PS422识别的磷酸化tau和Aβ的共定位很少。以上结果提示,SUMO-1在APP/PS1转基因AD小鼠脑内表达增加,并可能参与变性神经突起及老年斑形成的调节。
关键词: 老年性痴呆; 小泛素化修饰物-1; tau; β-淀粉样蛋白
分类号:R363
[Potential involvement of abnormal increased SUMO-1 in modulation of the formation of Alzheimer's disease senile plaques and neuritic dystrophy in APP/PS1 transgenic mice.] [Article in Chinese]
ZHAO Xiao-Yan, WANG Dan-Dan, SHAN Ye, ZHU Cui-Qing*
State Key Laboratory of Medical Neurobiology and Institutes of Brain Science, Fudan University, Shanghai 200032, China
Abstract
Small ubiquitin-related modifiers (SUMOs) belong to an important class of ubiquitin like proteins. SUMOylation is a post-translational modification process that regulates the functional properties of many proteins, among which are several proteins implicated in neurodegenerative diseases. This study was aimed to investigate the changes of SUMO-1 expression and modification, and the relationship between SUMO-1 and Alzheimer's disease (AD) pathology in APP/PS1 transgenic AD mice. Using Western blot, co-immunoprecipitation and immunofluorescent staining methods, the SUMO-1 expression and modification and its relation to tau, amyloid precursor protein (APP) and β-amyloid protein (Aβ) in the 12-month-old APP/PS1 transgenic AD mice were analyzed. The results showed that: (1) Compared with the normal wild-type mice, the expression and modification of SUMO-1 increased in brain of AD mice, which was accompanied by an increase of ubiquitination; (2) In RIPA soluble protein fraction of cerebral cortex, co-immunoprecipitation analysis showed tau SUMOylated by SUMO-1 increased in AD mice, however, AT8 antibody labeled phosphorylated tau was less SUMOylated whereas PS422 antibody labeled phosphorylated tau was similar to control mice; (3) Double immunofluorescent staining showed that SUMO-1 could distributed in amyloid plaques, appearing that some of SUMO-1 diffused in centre of some plaques and some of SUMO-1 co-localized with AT8 labeled phosphorylated tau forming punctate aggregates around amyloid plaques which was concerned as dystrophic neurites, however, less Aβ, APP and PS422 labeled phosphorylated tau were found co-localized with SUMO-1. These results suggest that SUMO-1 expression and modification increase abnormally in transgenic AD mice, which may participate in modulation of the formation of senile plaques and dystrophic neurites. Key words:
Alzheimer’s disease; small ubiquitin-related modifier-1; tau; β-amyloid protein 收稿日期:2012-10-09 录用日期:2013-01-18 通讯作者:朱粹青 E-mail: cqzhu@shmu.edu.cn 引用本文: 赵晓燕, 王丹丹, 单烨, 朱粹青. APP/PS1转基因鼠脑内小泛素化修饰物-1上调可能参与阿尔茨海默病老年斑形成和神经突起变性的调节[J]. 生理学报 2013; 65 (3): 253-262. ZHAO Xiao-Yan, WANG Dan-Dan, SHAN Ye, ZHU Cui-Qing. [Potential involvement of abnormal increased SUMO-1 in modulation of the formation of Alzheimer's disease senile plaques and neuritic dystrophy in APP/PS1 transgenic mice.]
[Article in Chinese]. Acta Physiol Sin 2013; 65 (3): 253-262 (in Chinese with English abstract).