1.国家卫生健康委员会人类疾病比较医学重点实验室,国家中医药管理局人类疾病动物模型三级实验室, 中国医学科学院医学实验动物研究所,北京协和医学院比较医学中心,北京 100021; 2.河北省法医学重点实验室,河北医科大学法医学院,河北省法医分子鉴定协同创新中心,石家庄 050017
R-33
WANG Manshi
1.Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences (CAMS); Comparative Medicine Center, Peking Union Medical College (PUMC); Key Laboratory of Human Disease Comparative Medicine, National Health Commission of the People’s Republic of China; Key Laboratory of Human Disease Animal Models, State Administration of Traditional Chinese Medicine, Beijing 100021, China. 2. Hebei Key Laboratory of Forensic Medicine; College of Forensic Medicine, Hebei Medical University; Hebei Collaborative InNovation Center of Forensic Medical Molecular Identifications, Shijiazhuang 050017ZHANG Ling
Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences (CAMS); Comparative Medicine Center, Peking Union Medical College (PUMC); Key Laboratory of Human Disease Comparative Medicine, National Health Commission of the People’s Republic of China; Key Laboratory of Human Disease Animal Models, State Administration of Traditional Chinese Medicine, Beijing 100021, ChinaQIN Chuan
Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences (CAMS); Comparative Medicine Center, Peking Union Medical College (PUMC); Key Laboratory of Human Disease Comparative Medicine, National Health Commission of the People’s Republic of China; Key Laboratory of Human Disease Animal Models, State Administration of Traditional Chinese Medicine, Beijing 100021, China1.Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences (CAMS); Comparative Medicine Center, Peking Union Medical College (PUMC); Key Laboratory of Human Disease Comparative Medicine, National Health Commission of the People’s Republic of China; Key Laboratory of Human Disease Animal Models, State Administration of Traditional Chinese Medicine, Beijing 100021, China. 2. Hebei Key Laboratory of Forensic Medicine; College of Forensic Medicine, Hebei Medical University; Hebei Collaborative InNovation Center of Forensic Medical Molecular Identifications, Shijiazhuang 050017
目的 探索 α-突触核蛋白 A53T 转基因小鼠认知功能,运动功能与焦虑样行为学的改变以及病理 学变化特点。 方法 选用背景为 C57BL/ 6 的 α-突触核蛋白 A53T 转基因小鼠作为实验组,同窝阴性小鼠为对照组。 采用旷场及圆筒实验检测小鼠的焦虑状态;转棒及抓力实验评价小鼠的运动协调能力以及前肢张力;水迷宫及条件恐惧实验评价小鼠的认知能力。 通过免疫组织化学染色法研究模型小鼠脑内病理特征;通过电镜观察模型小鼠脑内线粒体变化。 结果 与对照组比较,α-突触核蛋白 A53T 转基因小鼠运动距离增加,呈现过度活跃状态; 对条件恐惧记忆的时间缩短,出现认知障碍;圆筒、转棒与抓力实验及水迷宫实验未见统计学差异。模型组小鼠黑质、纹状体、梨状皮层及海马的 α-synuclein 磷酸化水平增加,前额叶路易小体沉积,黑质纹状体 α-synuclein 沉积增多,黑质 TH 阳性细胞数量显著减少;与对照组比较,电镜观察模型组小鼠脑内线粒体嵴及其内容物不清,线粒体形态改变。 结论 突触核蛋白 A53T 转基因小鼠出现认知功能受损,并且早于运动障碍发生;病理特征表现为 α- synuclein / LBs 沉积于前额叶、皮层,黑质多巴胺能神经元缺失以及线粒体形态改变,可作为一种突触核蛋白相关认知障碍性疾病如路易氏体痴呆和帕金森病痴呆的动物模型。
Objective To explore changes in motor coordination, cognitive function, and anxiety-like behavior as well as pathological characteristics in α-synuclein A53T transgenic mice. Methods We used α-synuclein A53T transgenic mice with a C57BL/ 6 background as the experimental group, and included a negative control group. The open field and cylinder tests were used to examine mouse anxiety levels, the rotarod and grip tests were used to evaluate movement disorders, and the Morris water maze and a fear conditioning test were used to evaluate cognitive ability. Pathological features were studied using immunohistochemical staining and mitochondrial morphology was observed via electron microscopy. Results Compared with the control group, α-synuclein A53T transgenic mice moved a greater distance, indicating that the mice were overactive. Further, freezing time was decreased, indicating cognitive impairment. We found no differences in performance in the cylinder test, rotarod test, grip test, or Morris water maze. In the α-synuclein A53T transgenic mice, levels of phosphorylated α-synuclein in the substantia nigra, striatum, piriform cortex, and hippocampus were increased, and we found Lewy bodies in the prefrontal cortex. Further, increased deposition of α-synuclein in the substantia nigra and striatum was observed, and the number of TH cells in the substantia nigra decreased significantly. Compared with the control group, mitochondria fission in the amygdala was increased, and the mitochondrial contents were unclear. Conclusions Cognitive function was impaired in α-synuclein A53T transgenic mice. Pathological characteristics included α-synuclein / LBs deposits in the prefrontal and piriform cortex, decreases in dopaminergic neurons in the substantia nigra, and altered mitochondrial morphology in the amygdala. α-synuclein A53T transgenic mice may be an appropriate model of synucleinopathy-related cognitive disease such as Lewy body dementia and dementia related to Parkinson’s disease.
王嫚诗,张 玲,秦 川,丛 斌.α-突触核蛋白 A53T 突变损伤小鼠认知功能[J].中国比较医学杂志,2020,30(5):7~13.
复制