Beta-amyloid accumulation in APP mutant neurons reduces PSD-95 and GluR1 in synapses
Beta-amyloid accumulation in APP mutant neurons reduces PSD-95 and GluR1 in synapses
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DOI：
10.1016/j.nbd.2005.02.008
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发表时间：
2005-11-01
影响因子：
6.1
通讯作者：
Gouras, GK
中科院分区：
文献类型：
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作者：
Almeida, CG;Tampellini, D;Gouras, GK
突触功能障碍越来越被视为阿尔茨海默病（AD）的早期表现，但β -淀粉样蛋白（A β）影响突触的细胞机制仍不清楚。由于来自APP突变转基因小鼠的培养神经元分泌的A β水平升高，并且与体内亚细胞A β积累相似，我们想知道在这种情况下突触是否会发生改变。我们报道，与野生型神经元相比，培养的Tg2576 APP突变神经元在突触前和突触后区室中具有选择性改变。突触后区室数量少、体积小，活跃的突触前区室数量少、体积大。APP突变神经元突触组成的最早变化是PSD-95的减少，PSD-95是一种参与招募和锚定谷氨酸受体亚基到突触后密度的蛋白质。与此一致的是，我们观察到APP突变神经元中谷氨酸受体亚基GluR1的表面表达早期减少。我们提供的证据表明，A β特异性参与突触生物学的这些改变，因为PSD-95和GluR1的改变被γ分泌酶抑制所阻断，并且由于外源添加合成A β到野生型神经元中，与APP突变神经元中观察到的突触PSD-95和GluR1的变化相似。(c) 2005爱思唯尔公司版权所有。
Synaptic dysfunction is increasingly viewed as an early manifestation of Alzheimer's disease (AD), but the cellular mechanism by which beta-amyloid (A beta) may affect synapses remains unclear. Since cultured neurons derived from APP mutant transgenic mice secrete elevated levels of A beta and parallel the subcellular A beta accumulation seen in vivo, we asked whether alterations in synapses occur in this setting. We report that cultured Tg2576 APP mutant neurons have selective alterations in pre- and post-synaptic compartments compared to wild-type neurons. Post-synaptic compartments appear fewer in number and smaller, while active pre-synaptic compartments appear fewer in number and enlarged. Among the earliest changes in synaptic composition in APP mutant neurons were reductions in PSD-95, a protein involved in recruiting and anchoring glutamate receptor subunits to the post-synaptic density. In agreement, we observed early reductions in surface expression of glutamate receptor subunit GluR1 in APP mutant neurons. We provide evidence that A beta is specifically involved in these alterations in synaptic biology, since alterations in PSD-95 and GluR1 are blocked by gamma-secretase inhibition, and since exogenous addition of synthetic A beta to wild-type neurons parallels changes in synaptic PSD-95 and GluR1 observed in APP mutant neurons. (c) 2005 Elsevier Inc. All rights reserved.