Effects of aerobic or resistance exercise on hippocampal ras/Drebrin dendritic spine plasticity in a mouse model of Alzheimer’s disease

doi:10.12307/2025.761

Abstract

Abstract: BACKGROUND: Studies have shown that there is a close relationship between dendritic spine plasticity and Alzheimer’s disease, and that resistance or aerobic exercise has some efficacy in improving cognitive dysfunction, but the mechanism of action is unclear.
OBJECTIVE: To investigate the effect of aerobic exercise or resistance exercise on dendritic spine plasticity in the hippocampal CA1 region of APP/PS1 transgenic mice.
METHODS: Thirty 3-month-old male APP/PS1 mice were selected and randomly divided into three groups: a model group, a resistance exercise group, and an aerobic exercise group. The same litter of 3-month-old C57BL/6J mice were selected as a blank group. Mice in the resistance exercise group were subjected to ladder-climbing exercise and those in the aerobic exercise group were subjected to treadmill exercise for 12 weeks. At the end of the exercise intervention, the water maze experiment and the new arm of the Y maze were used to assess behavioral changes in mice. Hematoxylin-eosin staining, Nissl staining, Golgi staining, and electron microscopy were performed to observe neuronal morphology, Nissl bodies, dendritic spines, and ultrastructural changes in the synapses of the hippocampal region of the mouse brain. The protein expression levels of hippocampal amyloid-beta1-42, Ras, and Drebrin were measured using Western blot analysis.
RESULTS AND CONCLUSION: Mice in the model group exhibited a prolonged escape latency over 5 consecutive days (P < 0.05, P < 0.01) and significantly fewer entries into the new arm of the Y maze (P < 0.01). Dendritic spine density in the CA1 region of the hippocampus, as well as Ras and Drebrin expression in the hippocampal tissues of mice in the model group, were lower than those in the normal group (P < 0.01), and amyloid-beta1-42 expression in the hippocampal tissues was higher in the model group compared with the normal group (P < 0.01). Mice in the resistance exercise group and the aerobic exercise group displayed a shortened escape latency over the same 5-day period (P < 0.05, P < 0.01) and showed a significantly greater number of entries into the new arm of the Y maze compared with the normal group (P < 0.01). Dendritic spine density in the CA1 region of the hippocampus, as well as Ras and Drebrin expression in the hippocampal tissues, were higher in both the resistance exercise group and the aerobic exercise group compared with the model group (P < 0.01).Amyloid-beta1-42 expression in the hippocampal tissue was lower in both exercise groups than in the model group (P < 0.01). To conclude, long-term regular aerobic or resistance exercise interventions can increase dendritic spine density and synaptic plasticity in the CA1 region of the hippocampus, enhancing spatial learning and memory abilities in a mouse model of Alzheimer’s disease. These effects may be associated with increased expression of Ras and Drebrin proteins in the hippocampus.

Key words: resistance exercise, aerobic exercise, dendritic spines, Drebrin, Ras, APP/PS1 mice, Alzheimer’s disease

CLC Number:

He Ningjuan, Li Li, Wang Su, Yang Jianshe, Lei Siyun, Wang Yang. Effects of aerobic or resistance exercise on hippocampal ras/Drebrin dendritic spine plasticity in a mouse model of Alzheimer’s disease[J]. Chinese Journal of Tissue Engineering Research, 2025, 29(26): 5528-5535.

Figures/Tables 4

2.1 实验动物数量分析实验选用APP/PS1双转基因30只，C57BL/6J小鼠10只，实验过程中无脱失，全部进入结果分析。 2.2 水迷宫实验结果 Morris水迷宫定位巡航实验显示，各组小鼠之间的游泳速度无明显差异(P > 0.05)，见图1A；表明游泳速度不会影响各组小鼠之间的逃避潜伏期差异。随着训练时间的增加，各组小鼠逃避潜伏期总体呈现下降趋势。从学习阶段第2天开始，与正常组对比，模型组小鼠连续5 d逃避潜伏期延长(P < 0.05，P < 0.01)；与模型组对比，抗阻运动组和有氧运动组小鼠连续5 d逃避潜伏期缩短(P < 0.05，P < 0.01)；与有氧运动组对比，抗阻运动组小鼠连续5 d逃避潜伏期无明显差异(P > 0.05)，见图1B；说明抗阻运动或有氧运动均可以有效改善小鼠的学习记忆能力。空间探索结果显示，与正常组对比，模型组小鼠穿越平台次数均减少(P < 0.01)；与模型组相比，抗阻运动组和有氧运动组小鼠穿越平台次数均有所增加(P < 0.05，P < 0.01)；与有氧运动组对比，抗阻运动组小鼠穿越平台次数无明显差异(P > 0.05)，见图1C，D。 2.3 Y迷宫实验结果 Y迷宫新臂探索实验的结果显示，与正常组比较，模型组小鼠进入Y迷宫新臂的次数显著减少(P < 0.01)；与模型组比较，抗阻运动组和有氧运动组小鼠进入Y迷宫新臂的次数明显增加(P < 0.05，P < 0.01)；与有氧运动组对比，抗阻运动组小进入Y迷宫新臂的次数无明显差异(P > 0.05)，见图2A。与正常组比较，模型组小鼠在新臂的探索时间缩短(P < 0.01)；与模型组比较抗阻运动组和有氧运动组小鼠在新臂的探索时间明显延长(P < 0.05，P < 0.01)；与有氧运动组对比，抗阻运动组小鼠在新臂的探索时间无明显延长(P > 0.05)，见图2B。此外，与正常组相比较，模型组小鼠总进臂次数明显减少(P < 0.01)，与模型组比较抗阻运动组和有氧运动组小鼠总进臂次数明显增加(P < 0.05，P < 0.01)，与有氧运动组对比，抗阻运动组总进臂次数无明显差异(P > 0.05)，见图2C。每组小鼠在新臂探索实验中的典型行动路线图见图2D。 2.4 苏木精-伊红/尼氏/高尔基染色结果见图3。 2.4.1 苏木精-伊红染色观察海马神经元细胞的形态变化正常组小鼠海马内CA1区锥体细胞排列紧密有序，结构完整，未见细胞形态发生明显病理改变。模型组小鼠海马内神经元细胞排列紊乱，核皱缩甚至破坏，细胞间隙明显增大，数量减少。抗阻运动组和有氧运动组小鼠海马CA1区神经元排列为整齐，核损伤数量较少，神经元形态较为完整，见图3A。 2.4.2 尼氏体观察神经元细胞损伤情况正常组小鼠海马区神经元排列整齐致密，形态规则，且神经元内尼氏体丰富，镜下多为标准的虎斑状或点状；模型小鼠海马区神经元排列紊乱、细胞之间的间隙较大，尼氏体数量明显减少；与模型组对比，抗阻运动组和有氧运动组小鼠海马区神经元形态均有所改善，排列较为整齐，尼氏体数量增多，染色加深，见图3B。与正常组相比较，模型组小鼠海马CA1区胞质内尼氏体数量明显减少(P < 0.01)；与模型组比较，抗阻运动组和有氧运动组海马CA1区胞质内尼氏体数量明显减少(P < 0.01，P < 0.05)；与有氧运动组对比，抗阻运动组海马CA1区胞质内尼氏体数量无明显差异(P > 0.05)，见图3E。 2.4.3 高尔基染色观察海马神经元及树突棘的形态结构正常组小鼠海马CA1区树突棘分布整齐密集，边缘完整；模型组小鼠海马CA1区神经元树突分支少，树突棘密度显著减少(P < 0.01)；抗阻运动组和有氧运动组小鼠海马CA1区神经元树突棘形态较为规则，密度显著增加(P < 0.01)，分布较为复杂，见图3C；与有氧运动组对比，抗阻运动组小鼠神经元树突棘密度增加(P < 0.05)，见图3D，F。结果说明，抗阻运动和有氧运动均可改善APP/PS1小鼠海马神经元树突损伤，且抗阻运动的改善效果更好。 2.5 各组小鼠海马CA1区突触超微结构变化见图4。突触是神经元之间传递信息和形成记忆的结构基础，电子透射显微镜观察结果发现，正常组小鼠海马CA1区突触结构完整、数量多；模型组小鼠海马CA1区突触数量明显减少、突触前膜与突触后膜分界线清晰度欠佳、突触活性带长度变短和突触后膜致密物减少，突触连接结构紊乱；抗阻运动组和有氧运动组小鼠海马CA1区突触数量增加，突触间隙缩短、突触有效长度增加，见图4D。与正常组对比，模型组小鼠海马CA1区突触间隙显著变大(P < 0.01)；与模型组相比，抗阻运动组小鼠CA1区突触间隙明显减少(P < 0.05)，有氧运动组小鼠突触间隙变化差异无显著性意义(P > 0.05)；与有氧运动组相比，抗阻运动组小鼠海马CA1突触间隙变化差异无显著性意义(P > 0.05)，见图4A。与正常组对比，模型组小鼠海马突触活性带长度显著变短(P < 0.01)；与模型组相比，抗阻运动组小鼠突触活性带长度明显增加(P < 0.05)；有氧运动组小鼠突触活性带长度变化差异无显著性意义(P > 0.05)；与有氧运动组相比，抗阻运动组小鼠海马CA1突触活性带长度变化差异无显著性意义(P > 0.05)，见图4B。与正常组对比，模型组小鼠海马突触后膜致密物厚度显著下降(P < 0.01)；与模型组相比，抗阻运动组和有氧运动组小鼠突触后膜致密物厚度显著增多(P < 0.01，P < 0.05)；与有氧运动组相比，抗阻运动组小鼠突触后膜致密物明显增多(P < 0.05)，见图4C。 2.6 Western Blot结果进一步通过Western Blot检测各组小鼠海马组织中β-淀粉样蛋白1-42蛋白、Ras蛋白和Drebrin蛋白表达，见图5A。与正常组对比，模型组小鼠海马Ras和Drebrin蛋白表达量降低(P < 0.01)；与模型组相比，抗阻运动组和有氧运动组小鼠海马Ras和Drebrin蛋白表达量升高明显(P < 0.05，P < 0.01)；与有氧运动组对比，抗阻运动组小鼠Ras和Drebrin蛋白表达量升高明显(P < 0.05)，见图5B，C。与正常组对比，模型组小鼠海马β-淀粉样蛋白1-42蛋白表达量升高(P < 0.01)；与模型组相比，抗阻运动组"

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