不同时程APP/PS1模型小鼠嗅球病理和突触形态变化及美金刚干预作用

doi:10.12300/j.issn.1674-5817.2022.001

实验动物与比较医学 ›› 2022, Vol. 42 ›› Issue (3): 177-186.DOI: 10.12300/j.issn.1674-5817.2022.001

不同时程APP/PS1模型小鼠嗅球病理和突触形态变化及美金刚干预作用

刘佳妮¹^,²^,³(), 刘剑刚¹(), 韦云¹()(), 罗增刚⁴, 李浩¹, 王怡³, 李琨⁵

^1.中国中医科学院西苑医院, 中国中医科学院老年病研究所, 北京 100091
^2.中国中医科学院研究生院, 北京 100700
^3.天津中医药大学, 天津 301617
^4.北京市中医管理局, 北京 100053
^5.北京开放大学, 北京 100081

收稿日期:2022-01-04 修回日期:2022-03-25 出版日期:2022-06-25 发布日期:2022-06-25
作者简介:刘佳妮（1992—），女，博士研究生，研究方向：老年病的中西医结合临床研究和基础研究。E-mail：liujiani1110@163.com
刘剑刚（1963—），男，研究员，研究生导师，研究方向：中药药理学及微循环学，心血管病的中西医结合临床研究和基础研究。E-mail：liujiangang2002@sina.com。ORCID：0000-0002-2313-4592
韦云（1981—），女，副主任医师，医学博士，研究生导师，研究方向：中西医结合老年病的临床研究和基础研究。E-mail：weiyun_0913@163.com。ORCID：0000-0001-9270-2701
基金资助:
国家自然科学青年基金项目：参芎解毒方干预外泌体介导的Tau蛋白脑区扩散致阿尔茨海默病嗅觉及认知障碍的机制研究(81904194)

Pathological and Synaptic Morphological Changes of the Olfactory Bulb in APP/PS1 Model Mice at Different Ages and the Intervention Effect of Memantine

Jiani LIU¹^,²^,³(), Jiangang LIU¹(), Yun WEI¹()(), Hao LI⁴, Zenggang LUO¹, Yi WANG³, Kun LI⁵

^1.Xiyuan Hospital, Institute of Geriatrics, China Academy of Chinese Medical Sciences, Beijing 100091, China
^2.Graduate School of China Academy of Chinese Medical Sciences, Beijing 100700, China
^3.Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
^4.Beijing Administration of Traditional Chinese Medicine, Beijing 100053, China
^5.Beijing Open University, Beijing 100081, China

Received:2022-01-04 Revised:2022-03-25 Published:2022-06-25 Online:2022-06-25
About author:LIU Jiangang E-mail: liujiangang2002@sina.com
WEI Yun E-mail: weiyun_0913@163.com

摘要/Abstract

摘要：

目的比较和探讨6月龄和12月龄的APP/PS1双转基因模型小鼠嗅球组织病理形态、超微结构特征、空间记忆能力的变化以及美金刚干预的作用。方法将SPF级3月龄雄性APP/PS1小鼠按随机数字表法分为6月龄、12月龄的模型组（分别为命名为6-APP/PS1组、12-APP/PS1组）和盐酸美金刚（memantine hydrochloride，MEM）干预组（分别命名为6-MEM组、12-MEM组，MEM剂量均为2.60 mg/kg/d），每组10只。另设同龄C57BL/6小鼠作为空白对照组。MEM连续（分别自3月龄和9月龄）灌胃3个月，非MEM处理小鼠接受等容积纯净水灌胃。于6月龄和12月龄时进行Morris水迷宫实验检测，固定取材进行HE染色后光学显微镜下观察嗅球病理组织形态，超薄切片染色后透射电子显微镜下观察嗅球超微结构。结果水迷宫结果显示，与同龄的空白对照组比较，6-APP/PS1组和12-APP/PS1组小鼠的穿台次数、穿梭目标象限的时间及路程明显降低（均P＜0.05），且12-APP/PS1组比6-APP/PS1组的降低程度更明显（均P＜0.05）；与同龄的模型组比较，6-MEM组和12-MEM组的穿台次数、目标象限停留时间及路程显著提高（均P＜0.05）。组织病理学观察发现，与同龄的空白对照组比较，6-APP/PS1组小鼠嗅球的神经细胞无明显萎缩变形且僧帽细胞数量显著减少（P＜0.05），12-APP/PS1组小鼠嗅球的神经细胞萎缩变形且球周细胞、僧帽细胞数量显著减少（均P＜0.05）；与同龄模型组比较，6-MEM组球周细胞无显著增多但僧帽细胞数量显著增多（P＜0.05），12-MEM组球周细胞、僧帽细胞数量有增加趋势但差异无统计学意义（均P＞0.05）。超微结构观察显示，与同龄的空白对照组比较，6-APP/PS1组突触结构出现肿胀，突触后致密物厚度及非对称性突触数量减少；12-APP/PS1组突触结构肿胀，非对称性突触及突触后致密物厚度无法观测。与同龄模型组比较，6-MEM组突触肿胀改善明显，突触后致密物厚度及非对称性突触数量增加；12-MEM组突触肿胀改善不明显，突触后致密物及非对称性突触无法观测。结论随月龄增加，不同时程的APP/PS1小鼠出现了阿尔茨海默病相关的行为学改变，同时伴随嗅球病理及突触特征的显著变化。MEM干预不仅改善空间记忆能力，还可增加6-APP/PS1小鼠嗅球的僧帽细胞数量，减轻突触结构损伤，早期干预的改善效果显著。

关键词: 阿尔茨海默病, APP/PS1转基因小鼠, 嗅球, 突触, 病理形态

Abstract:

Objective To compare and explore the histopathological and ultrastructural characteristics of the olfactory bulb in 6- and 12-month-old APP/PS1 double-transgenic mice and their spatial learning and memory ability, as well as the effects of memantine intervention.Methods Three-month-old SPF male APP/PS1 mice were randomly divided into 6- and 12-month-old model groups (named 6-APP/PS1 group and 12-APP/PS1 group, respectively) and memantine (MEM) groups (named 6-MEM group and 12-MEM group, respectively, the dose of MEM was 2.60 mg/kg/d), with 10 mice in each group. Age-matched C57BL/6 mice were used as the blank controls. The mice in the MEM groups were continuously administered MEM (from 3 months and 9 months, respectively) by gavage for 3 months, and the mice in the non-MEM group received equal volume of pure water for 3 months. The Morris water maze test was used to assess spatial learning and memory ability of those mice at 6 months and 12 months of age. After hematoxylin-eosin staining, the pathological morphology of the olfactory bulb was observed under an optical microscope, and the ultrastructure of the olfactory bulb was observed under a transmission electron microscope.Results The results of the water maze test revealed that the crossing numbers and the time spent in the target quadrant were significantly decreased in the 6-APP/PS1 and 12-APP/PS1 groups compared with the blank control group of the same age (all P < 0.05), whereas the 12-APP/PS1 group showed a more significant decrease than the 6-APP/PS1 group (both P < 0.05). Compared with the non-MEM group, the two parameters of the MEM treatment groups increased significantly (all P < 0.05). Histopathological observation showed that, compared with the age-matched blank group, the nerve cells in the olfactory bulb had no obvious atrophy and deformation, and the number of mitral cells was significantly reduced in the 6-APP/PS1 group (P < 0.05), while the nerve cells in the olfactory bulb were atrophic and deformed, and the number of periglomerular cells and mitral cells were significantly reduced in the 12-APP/PS1 group (all P < 0.05). Compared with the non-MEM group, the number of mitral cells were significantly increased in the 6-APP/PS1 group (P < 0.05), but there was no significant difference in the number of periglomerular cells and mitral cells in the 12-MEM group (all P > 0.05). Ultrastructural observation showed that, compared with the blank control group, the synaptic structure was swollen in the 6-APP/PS1 and 12-APP/PS1 groups, the thickness of the postsynaptic density was reduced and the number of asymmetric synapses decreased in the 6-APP/PS1 group, while the thickness of the postsynaptic density and the number of asymmetric synapses could not be observed clearly in the 12-APP/PS1 group. Compared with the non-MEM group, the synaptic swelling in the 6-MEM group was significantly improved, the thickness of the postsynaptic density and the number of asymmetric synapses increased, but the synaptic swelling in the 12-MEM group was not significantly improved, and the thickness of the postsynaptic density and the number of asymmetric synapses could not be observed.Conclusion Changes in the pathology and synaptic ultrastructural morphology of the olfactory bulbs in the APP/PS1 mice correlated with age, accompanied by behavioral alterations. MEM intervention not only improved spatial memory ability in the APP/PS1 mice, but also increased the number of mitral cells and alleviated the damage to the synaptic structure in the 6-APP/PS1 group, with significant improvement in early intervention.

Key words: Alzheimer's disease, APP/PS1 transgenic mice, Olfactory bulb, Synapses, Pathological morphology

中图分类号:

R-332

刘佳妮,刘剑刚,韦云,等. 不同时程APP/PS1模型小鼠嗅球病理和突触形态变化及美金刚干预作用[J]. 实验动物与比较医学, 2022, 42(3): 177-186. DOI: 10.12300/j.issn.1674-5817.2022.001.

Jiani LIU,Jiangang LIU,Yun WEI,et al. Pathological and Synaptic Morphological Changes of the Olfactory Bulb in APP/PS1 Model Mice at Different Ages and the Intervention Effect of Memantine[J]. Laboratory Animal and Comparative Medicine, 2022, 42(3): 177-186. DOI: 10.12300/j.issn.1674-5817.2022.001.

图/表 4

注：A图示不同时程各组小鼠的穿台次数、目标象限路程、目标象限时间和总路程；B图示各组小鼠在水迷宫中游动轨迹（绿色线圈为原逃生平台位置，红色方块为入水点，蓝色方块为90 s截止录制点）。6-C57指6月龄的空白对照组C57BL/6小鼠；6-APP/PS1指6月龄的模型组APP/PS1双转基因小鼠；6-MEM指从3月龄开始用2.6 mg/kg盐酸美金刚干预至6月龄的APP/PS1双转基因小鼠；12-C57指12月龄的空白对照组C57BL/6小鼠；12-APP/PS1指12月龄的模型组APP/PS1双转基因小鼠；12-MEM指从9月龄开始用2.6 mg/kg盐酸美金刚干预至12月龄的APP/PS1双转基因小鼠。每组10只小鼠。与6-C57相比，^*P < 0.05；与12-C57相比，^#P < 0.05；与6-APP/PS1相比，^△P < 0.05；与12-APP/PS1相比，^&P < 0.05。
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图1 Morris水迷宫实验评估各组小鼠的行为学变化
注：A图示不同时程各组小鼠的穿台次数、目标象限路程、目标象限时间和总路程；B图示各组小鼠在水迷宫中游动轨迹（绿色线圈为原逃生平台位置，红色方块为入水点，蓝色方块为90 s截止录制点）。6-C57指6月龄的空白对照组C57BL/6小鼠；6-APP/PS1指6月龄的模型组APP/PS1双转基因小鼠；6-MEM指从3月龄开始用2.6 mg/kg盐酸美金刚干预至6月龄的APP/PS1双转基因小鼠；12-C57指12月龄的空白对照组C57BL/6小鼠；12-APP/PS1指12月龄的模型组APP/PS1双转基因小鼠；12-MEM指从9月龄开始用2.6 mg/kg盐酸美金刚干预至12月龄的APP/PS1双转基因小鼠。每组10只小鼠。与6-C57相比，^*P < 0.05；与12-C57相比，^#P < 0.05；与6-APP/PS1相比，^△P < 0.05；与12-APP/PS1相比，^&P < 0.05。

Figure 1 Morris water maze test to evaluate the behavioral changes of mice in each group
Note： Fig. A shows the crossing numbers， distance in the target quadrant， time spent in the target quadrant， and the total distance of mice in each group. Fig. B shows the swimming track of mice in each group in the water maze （the green circle represents the position of the original escape platform， the red dot represents the entry point， and the blue dot represents the 90 s cut-off point）. 6-C57 refers to 6-month-old C57BL/6 mice in the blank control group. 6-APP/PS1 refers to 6-month-old APP/PS1 double transgenic mice in the model group； 6-MEM refers to APP/PSI double transgenic mice treated with 2.6 mg/kg memantine hydrochloride from 3- to 6-month-old； 12-C57 refers to 12-month-old C57BL/6 mice； 12-APP/PS1 refers to 12-month-old APP/PS1 double transgenic mice； 12-MEM refers to APP/PS1 double transgenic mice treated with 2.6 mg/kg memantine hydrochloride from 9- to 12-month-old. Each group contained 10 mice. Compared with 6-C57， ^*P < 0.05； compared with 12-C57， ^#P < 0.05； compared with 6-APP/PS1， ^△P < 0.05； compared with 12-APP/PS1， ^&P < 0.05.

注：图a示低倍镜下嗅球（×40），图b示高倍镜下小球层（×200），图c示高倍镜下僧帽细胞层（×200）。箭头①为突触小球，箭头②为球周细胞，箭头③为僧帽细胞。6-C57指6月龄的空白对照组C57BL/6小鼠；6-APP/PS1指6月龄的模型组APP/PS1双转基因小鼠；6-MEM指从3月龄开始用2.6 mg/kg盐酸美金刚干预至6月龄的APP/PS1双转基因小鼠；12-C57指12月龄的空白对照组C57BL/6小鼠；12-APP/PS1指12月龄的模型组APP/PS1双转基因小鼠；12-MEM指从9月龄开始用2.6 mg/kg盐酸美金刚干预至12月龄的APP/PS1双转基因小鼠。每组5只小鼠。
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图2 HE染色后光学显微镜观察各组小鼠的嗅球病理变化
注：图a示低倍镜下嗅球（×40），图b示高倍镜下小球层（×200），图c示高倍镜下僧帽细胞层（×200）。箭头①为突触小球，箭头②为球周细胞，箭头③为僧帽细胞。6-C57指6月龄的空白对照组C57BL/6小鼠；6-APP/PS1指6月龄的模型组APP/PS1双转基因小鼠；6-MEM指从3月龄开始用2.6 mg/kg盐酸美金刚干预至6月龄的APP/PS1双转基因小鼠；12-C57指12月龄的空白对照组C57BL/6小鼠；12-APP/PS1指12月龄的模型组APP/PS1双转基因小鼠；12-MEM指从9月龄开始用2.6 mg/kg盐酸美金刚干预至12月龄的APP/PS1双转基因小鼠。每组5只小鼠。

Figure 2 Pathological changes of the olfactory bulb in mice in each group observed by optical microscopy after hematoxylin-eosin staining
Note： Fig. a is the olfactory bulb （×40）； Fig. b is the glomerular layer （×200）； Fig. c is the mitral cell layer （×200）. Arrows ①， ②， and ③ show glomeruli， periglomerular， and mitral cells， respectively. 6-C57 refers to 6-month-old C57BL/6 mice in the blank control group； 6-APP/PS1 refers to 6-month-old APP/PS1 double transgenic mice in the model group； 6-MEM refers to APP/PSI double transgenic mice treated with 2.6 mg/kg memantine hydrochloride from 3- to 6-month-old； 12-C57 refers to 12-month-old C57BL/6 mice； 12-APP/PS1 refers to 12-month-old APP/PS1 double transgenic mice； 12-MEM refers to APP/PS1 double transgenic mice treated with 2.6 mg/kg memantine hydrochloride from 9- to 12-month-old. Each group contained five mice.

注：6-C57指6月龄的空白对照组C57BL/6小鼠；6-APP/PS1指6月龄的模型组APP/PS1双转基因小鼠；6-MEM指从3月龄开始用2.6 mg/kg盐酸美金刚干预至6月龄的APP/PS1双转基因小鼠；12-C57指12月龄的空白对照组C57BL/6小鼠；12-APP/PS1指12月龄的模型组APP/PS1双转基因小鼠；12-MEM指从9月龄开始用2.6 mg/kg盐酸美金刚干预至12月龄的APP/PS1双转基因小鼠。每组5只小鼠。与6-C57相比，^*P < 0.05；与12-C57相比，^#P < 0.05；与6-APP/PS1相比，^△P <0.05；与12-APP/PS1相比，^&P < 0.05。
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图3 美金刚对球周细胞（A）和僧帽细胞（B）的影响
注：6-C57指6月龄的空白对照组C57BL/6小鼠；6-APP/PS1指6月龄的模型组APP/PS1双转基因小鼠；6-MEM指从3月龄开始用2.6 mg/kg盐酸美金刚干预至6月龄的APP/PS1双转基因小鼠；12-C57指12月龄的空白对照组C57BL/6小鼠；12-APP/PS1指12月龄的模型组APP/PS1双转基因小鼠；12-MEM指从9月龄开始用2.6 mg/kg盐酸美金刚干预至12月龄的APP/PS1双转基因小鼠。每组5只小鼠。与6-C57相比，^*P < 0.05；与12-C57相比，^#P < 0.05；与6-APP/PS1相比，^△P <0.05；与12-APP/PS1相比，^&P < 0.05。

Figure 3 Effects of memantine on periglomerular cells （A） and mitral cells （B）
Note： 6-C57 refers to 6-month-old C57BL/6 mice in the blank control group； 6-APP/PS1 refers to 6-month-old APP/PS1 double transgenic mice in model group； 6-MEM refers to APP/PSI double transgenic mice treated with 2.6 mg/kg memantine hydrochloride from 3- to 6-month-old； 12-C57 refers to 12-month-old C57BL/6 mice； 12-APP/PS1 refers to 12-month-old APP/PS1 double trans-genic mice； 12-MEM refers to APP/PS1 double transgenic mice treated with 2.6 mg/kg memantine hydrochloride from 9- to 12-month-old. Each group contained five mice. Compared with 6-C57， ^*P < 0.05； compared with 12-C57， ^#P < 0.05； compared with 6-APP/PS1， ^△P < 0.05； compared with 12-APP/PS1， ^&P < 0.05.

注：6-C57指6月龄的空白对照组C57BL/6小鼠；6-APP/PS1指6月龄的模型组APP/PS1双转基因小鼠；6-MEM指从3月龄开始用2.6 mg/kg盐酸美金刚干预至6月龄的APP/PS1双转基因小鼠；12-C57指12月龄的空白对照组C57BL/6小鼠；12-APP/PS1指12月龄的模型组APP/PS1双转基因小鼠；12-MEM指从9月龄开始用2.6 mg/kg盐酸美金刚干预至12月龄的APP/PS1双转基因小鼠。每组5只小鼠。箭头①示对称性突触，箭头②示突触小泡（内含抑制性神经递质），箭头③示非对称性突触，箭头④示突触小泡（内含兴奋性神经递质）。
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图4 超薄切片染色后透射电子显微镜观察各组小鼠嗅球神经（A，×7 000）和突触（B，×60 000）细胞超微结构
注：6-C57指6月龄的空白对照组C57BL/6小鼠；6-APP/PS1指6月龄的模型组APP/PS1双转基因小鼠；6-MEM指从3月龄开始用2.6 mg/kg盐酸美金刚干预至6月龄的APP/PS1双转基因小鼠；12-C57指12月龄的空白对照组C57BL/6小鼠；12-APP/PS1指12月龄的模型组APP/PS1双转基因小鼠；12-MEM指从9月龄开始用2.6 mg/kg盐酸美金刚干预至12月龄的APP/PS1双转基因小鼠。每组5只小鼠。箭头①示对称性突触，箭头②示突触小泡（内含抑制性神经递质），箭头③示非对称性突触，箭头④示突触小泡（内含兴奋性神经递质）。

Figure 4 Ultrastructure of the olfactory bulb nerve cells （A， ×7 000） and synapses （B， ×60 000） in each group observed by transmission electron microscope after ultrathin section staining
Note： 6-C57 refers to 6-month-old C57BL/6 mice in the blank control group； 6-APP/PS1 refers to 6-month-old APP/PS1 double transgenic mice in model group； 6-MEM refers to APP/PSI double transgenic mice treated with 2.6 mg/kg memantine hydrochloride from 3- to 6-month-old； 12-C57 refers to 12-month-old C57BL/6 mice； 12-APP/PS1 refers to 12-month-old APP/PS1 double transgenic mice； 12-MEM refers to APP/PS1 double transgenic mice treated with 2.6 mg/kg memantine hydrochloride from 9- to 12-month-old. Each group contained five mice. Arrows ① show symmetric synapses， arrows ② show synaptic vesicles （containing inhibitory neurotransmitters）， arrows ③ show asymmetric synapses， and arrows ④ show synaptic vesicles （containing excitatory neurotransmitters）.

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不同时程APP/PS1模型小鼠嗅球病理和突触形态变化及美金刚干预作用

Pathological and Synaptic Morphological Changes of the Olfactory Bulb in APP/PS1 Model Mice at Different Ages and the Intervention Effect of Memantine

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