Age-Dependent Shift of AMPA Receptors From Synapses to Intracellular Compartments in Alzheimer's Disease: Immunocytochemical Analysis of the CA1 Hippocampal Region in APP/PS1 Transgenic Mouse Model.
Age-Dependent Shift of AMPA Receptors From Synapses to Intracellular Compartments in Alzheimer's Disease: Immunocytochemical Analysis of the CA1 Hippocampal Region in APP/PS1 Transgenic Mouse Model.
复制标题
DOI：
10.3389/fnagi.2020.577996
复制
发表时间：
2020
影响因子：
4.8
通讯作者：
Luján R
中科院分区：
文献类型：
--
作者：
Martín-Belmonte A;Aguado C;Alfaro-Ruíz R;Itakura M;Moreno-Martínez AE;de la Ossa L;Molnár E;Fukazawa Y;Luján R
突触丢失在阿尔茨海默病（AD）患者和动物模型中早期发生。突触水平的改变是记忆缺陷和AD相关症状的主要形态学相关性。鉴于突触AMPA受体（AMPAR）在大脑兴奋性突触传递中的主要作用，其动态调节的变化也与AD的病理生理学有关。本研究采用免疫组织化学技术，对APP/PS1小鼠AD模型海马区AMPAR的表达和亚细胞分布进行了研究。免疫印迹和组织印迹显示，在APP/PS1小鼠和年龄匹配的野生型小鼠中，海马中AMPAR的总量及其区域表达模式相似。在超微结构水平上，使用SDS消化的冷冻断裂复制品标记在小鼠放射层中检查两个突触群体：（i）在CA 1锥体细胞的棘上;和（ii）在随机发现的CA 1中间神经元的树突轴上。虽然1个月和6个月大的APP/PS1小鼠没有表现出任何变化，但我们观察到，与野生型相比，12个月大时锥体细胞和中间神经元突触处的AMPAR密度显著降低。树突棘中AMPAR的减少伴随着细胞内区室中AMPAR亚基蛋白的显著增加。我们的数据表明APP/PS1小鼠中突触AMPAR的年龄依赖性减少，这可能有助于AD后期的学习和记忆受损。
Synapse loss occurs early in Alzheimer’s disease (AD) patients and animal models. Alterations at synaptic level are a major morphological correlate of the memory deficits and related symptoms of AD. Given the predominant roles of synaptic AMPA receptors (AMPARs) in excitatory synaptic transmission in the brain, changes in their dynamic regulation are also implicated in the pathophysiology of AD. Here, we used immunolocalization techniques to analyze the expression and subcellular distribution of AMPARs in the hippocampal region of APP/PS1 mouse model of AD. Immunoblots and histoblots revealed that the total amount of AMPARs and their regional expression pattern in the hippocampus was similar in APP/PS1 mice and in age-matched wild type mice. At the ultrastructural level, two synapse populations were examined using SDS-digested freeze-fracture replica labeling in the stratum radiatum in mice: (i) on spines of CA1 pyramidal cells; and (ii) on randomly found dendritic shafts of CA1 interneurons. While 1- and 6-months-old APP/PS1 mice exhibited no change, we observed a significant reduction at 12 months in AMPAR density at synapses in both pyramidal cells and interneurons, compared to wild-type. This reduction of AMPARs in dendritic spines was accompanied by a significant increase in AMPAR subunit proteins identified in intracellular compartments. Our data demonstrate an age-dependent reduction of synaptic AMPARs in APP/PS1 mice, which may contribute to impaired learning and memory at later stages of AD.
登录
查看更多内容
影响因子：
7.8
作者：
Baglietto-Vargas D;Prieto GA;Limon A;Forner S;Rodriguez-Ortiz CJ;Ikemura K;Ager RR;Medeiros R;Trujillo-Estrada L;Martini AC;Kitazawa M;Davila JC;Cotman CW;Gutierrez A;LaFerla FM
通讯作者：
LaFerla FM
影响因子：
2.9
作者：
DEWAR, D;CHALMERS, DT;MCCULLOCH, J
通讯作者：
MCCULLOCH, J
影响因子：
5.3
作者：
Antal, Miklos;Fukazawa, Yugo;Shigemoto, Ryuichi
通讯作者：
Shigemoto, Ryuichi
影响因子：
6.1
作者：
Almeida, CG;Tampellini, D;Gouras, GK
通讯作者：
Gouras, GK
影响因子：
3.3
作者：
Brady, DR;Mufson, EJ
通讯作者：
Mufson, EJ