Glutamate receptor delocalization in postsynaptic membrane and reduced hippocampal synaptic plasticity in the early stage of Alzheimer's disease
Glutamate receptor delocalization in postsynaptic membrane and reduced hippocampal synaptic plasticity in the early stage of Alzheimer's disease
复制标题
阿尔茨海默病早期突触后膜谷氨酸受体离域和海马突触可塑性降低
DOI：
10.4103/1673-5374.250625
复制
发表时间：
2019-06-01
影响因子：
6.1
通讯作者：
Wang, Xiao-Min
中科院分区：
文献类型：
--
作者：
Li, Ning;Li, Yang;Wang, Xiao-Min
越来越多的证据表明，突触可塑性提供了学习和记忆的细胞生物学基础，可塑性缺陷在阿尔茨海默病引起的痴呆中起着关键作用。然而，突触功能障碍导致阿尔茨海默病发病机制的机制仍不清楚。在本研究中，阿尔茨海默氏病转基因小鼠被用来确定海马突触可塑性降低和病理变化和认知行为恶化之间的关系，以及潜在的突触可塑性降低的可能机制在早期阶段的阿尔茨海默氏病样疾病。在本研究中使用APP/PSI双转基因（5XFAD;杰克逊实验室）小鼠及其幼仔（野生型，对照）。另外6周龄和10周龄的5XFAD小鼠和野生型小鼠用于海马齿状回的电生理记录。对于10周龄的5XFAD小鼠和野生型小鼠，左侧海马用于电生理记录，右侧海马用于生化实验或免疫组织化学染色，以观察突触素水平和淀粉样蛋白β沉积水平。结果显示，与野生型小鼠相比，6周龄的5XFAD小鼠在海马齿状回中表现出未改变的长时程增强。另一组5XFAD小鼠在10周龄时开始表现出衰减，海马细胞中积累了大量的淀粉样β蛋白。α-氨基-3-羟基-5-甲基异恶唑-4-丙酸受体和N-甲基-D-天冬氨酸受体亚单位在突触体中的定位减少。这些发现表明，突触后谷氨酸受体的离域和相关的突触可塑性下降可能是阿尔茨海默病早期发病的关键机制。动物的使用和护理严格遵循中国首都医科大学动物伦理委员会于2015年12月17日发布的伦理标准（批准号AEEI-2015-182）。
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 Alzhehner's disease-like diseases. APP/PSI double transgenic (5XFAD; Jackson Laboratory) mice and their littennates (wild-type, controls) were used in this study. Additional 6-weekold and 10-week-old 5XFAD mice and wild-type mice were used for electrophysiological recording of hippocampal dentate gyms. For 10-week-old 5XFAD mice and wild-type mice, the left hippocampus was used for electrophysiological recording, and the right hippocampus 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 alpha-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 Capital Medical University, China on December 17, 2015 (approval No. AEEI-2015-182).