中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2019, Vol. 14 ›› Issue (6): 1037-1045.doi: 10.4103/1673-5374.250625

• 原著:退行性病与再生 • 上一篇    下一篇

阿尔茨海默病发病早期可出现突触后膜谷氨酸受体定位减少与海马突触可塑性降低

  

  • 出版日期:2019-06-15 发布日期:2019-06-15
  • 基金资助:

    国家自然科学基金(81571038 , 81771145)

Glutamate receptor delocalization in postsynaptic membrane and reduced hippocampal synaptic plasticity in the early stage of Alzheimer’s disease

Ning Li 1, 2, 3 , Yang Li 1, 2, 3 , Li-Juan Li 2, 3, 4 , Ke Zhu 2, 3, 4 , Yan Zheng 2, 3, 4 , Xiao-Min Wang 1, 2, 3   

  1. 1 Department of Neurobiology, Capital Medical University, Beijing, China
    2 Key Laboratory for Neurodegenerative Disorders of the Ministry of Education, Capital Medical University, Beijing, China
    3 Beijing Institute for Brain Disorders, Beijing, China
    4 Department of Physiology, Capital Medical University, Beijing, China
  • Online:2019-06-15 Published:2019-06-15
  • Contact: Yan Zheng, PhD, zhengyan@ccmu.edu.cn; Xiao-Min Wang, PhD, xmwang@ccmu.edu.cn.
  • Supported by:

    This study was supported by the National Natural Science Foundation of China, No. 81571038 , 81771145 (both to YZ).

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摘要：

已有证据显示突触可塑性是学习记忆的细胞学基础，并且其功能降低是阿尔茨海默病痴呆发生的重要环节，但其如何参与阿尔茨海默病早期病程的机制仍需探讨。实验采用阿尔茨海默病转基因鼠明确海马突触可塑性降低与阿尔茨海默病样病理改变及认知行为衰退之间的先后关系，拟揭示阿尔茨海默病样病程早期突触可塑性降低的可能机制。所用实验动物为Jackson Laboratory公司提供的APP/PS1双转基因小鼠(5XFAD)，取其同窝野生(WT)小鼠作为对照。将6周龄和10周龄5XFAD和WT小鼠用于脑片海马齿状回区电生理记录，对于10周龄5XFAD和WT小鼠，取左侧海马进行电生理记录的同时，将右侧海马组织用于生化实验或免疫组织化学染色观察，检测突触蛋白水平和β淀粉样蛋白的沉积水平。(1)结果显示：与WT小鼠相比，6周龄5XFAD小鼠并未出现海马齿状回长时程增强，10周龄5XFAD小鼠开始出现衰减现象，同时海马细胞内有大量β淀粉样蛋白聚集，AMPA受体和NMDA受体的亚基在突触小体的定位减少；(2)结果证实，海马突触后谷氨酸受体在突触后膜定位减少及其相关的突触可塑性降低，可能是阿尔茨海默病发病早期的关键靶点。

orcid: 0000-0002-0864-069X (Yan Zheng)
           0000-0002-0887-9238 (Xiao-Min Wang)

关键词: 阿尔茨海默病, 突触可塑性, 海马, 学习记忆, 长时程增强, &beta, 淀粉样蛋白, 谷氨酸受体, 突触强度, 神经再生

Abstract:

Mounting evidence suggests that synaptic plasticity provides the cellular biological basis of learning and memory, and plasticity deficits play a key role in dementia caused by Alzheimer’s disease. However, the mechanisms by which synaptic dysfunction contributes to the pathogenesis of Alzheimer’s disease remain unclear. In the present study, Alzheimer’s disease transgenic mice were used to determine the relationship between decreased hippocampal synaptic plasticity and pathological changes and cognitive-behavioral deterioration, as well as possible mechanisms underlying decreased synaptic plasticity in the early stages of Alzheimer’s disease-like diseases. APP/PS1 double transgenic (5XFAD; Jackson Laboratory) mice and their littermates (wild-type, controls) were used in this study. Additional 6-week-old and 10-week-old 5XFAD mice and wild-type mice were used for electrophysiological recording of hippocampal dentate gyrus. For 10-week-old 5XFAD mice and wild-type mice, the left hippocampus was used for electrophysiological recording, and the right hippocam¬pus was used for biochemical experiments or immunohistochemical staining to observe synaptophysin levels and amyloid beta deposition levels. The results revealed that, compared with wild-type mice, 6-week-old 5XFAD mice exhibited unaltered long-term potentiation in the hippocampal dentate gyrus. Another set of 5XFAD mice began to show attenuation at the age of 10 weeks, and a large quantity of amyloid beta protein was accumulated in hippocampal cells. The location of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor and N-methyl-D-aspartic acid receptor subunits in synaptosomes was decreased. These findings indicate that the delocalization of postsynaptic glutamate receptors and an associated decline in synaptic plasticity may be key mechanisms in the early onset of Alzheimer’s disease. The use and care of animals were in strict accordance with the ethical standards of the animal ethics committee of the Capital Medical Univer¬sity, China on December 17, 2015 (ethics No. AEEI-2015-182).

Key words: nerve regeneration, Alzheimer’s disease, synaptic plasticity, hippocampus, learning and memory, long-term potentiation, &beta, amyloid, glutamate receptor, synaptic strength, neural regeneration