Deregulation of NMDA-receptor function and down-stream signaling in APP[V717I] transgenic mice
Deregulation of NMDA-receptor function and down-stream signaling in APP[V717I] transgenic mice
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DOI：
10.1016/j.neurobiolaging.2007.06.011
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发表时间：
2009-02-01
影响因子：
4.2
通讯作者：
Van Leuven, F.
中科院分区：
文献类型：
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作者：
Dewachter, I.;Filipkowski, R. K.;Van Leuven, F.
越来越多的证据表明，淀粉样肽在突触可塑性和认知受损中发挥了作用，但其潜在机制尚不清楚。我们在此分析了淀粉样多肽在体外和体内对NMDA受体功能的影响。一种合成的含有单体和寡聚体Aβ(1-42)多肽的淀粉样肽制剂被用来与培养的海马神经元和皮质神经元中表达NMDA受体的突触结合。原代培养的神经细胞与Aβ多肽共同孵育可显著抑制NMDA受体功能。尽管不是通过对NMDA受体的直接药理抑制，因为急性应用Aβ肽并不改变自闭性海马区培养的NMDA受体电流，也不改变表达重组NMDA受体的非洲爪哇卵母细胞的NMDA受体电流。然而，用Aβ多肽预先孵育原代培养的神经元，会减少NR2B免疫反应的突触棘突和含有NMDA受体的NR2B的表面表达。更重要的是。我们首次在活体内扩展了这些发现。在APP[V717I]转基因小鼠的突触后密度准备中，NMDA受体亚单位NR2B和PSD-95以及激活的α-CaMKII的浓度降低。这与APP[V717I]转基因小鼠海马CA1区NMDA依赖LTP受损和NMDA和AMPA受体电流减少有关。此外，在APP[V717I]转基因小鼠的杏仁基底外侧核和海马区，线索和情景恐惧条件作用下c-Fos的诱导显著受损。我们的研究结果表明，APP[V717I]转基因小鼠体内存在NMDA受体功能缺陷和学习依赖信号的级联反应，并指出NMDA受体表面表达减少是APP[V717I]转基因小鼠早期突触缺陷的机制之一。(C)2007 Elsevier Inc.保留所有权利。
Evidence is accumulating for a role for amyloid peptides in impaired synaptic plasticity and cognition, While the Underlying mechanisms remain unclear. We here analyzed the effects of amyloid peptides oil NMDA-receptor function in vitro and in vivo. A synthetic amyloid peptide preparation containing monomeric and oligomeric A beta (1-42) peptides was used and demonstrated to bind to synapses expressing NMDA-receptors ill Cultured hippocampal and cortical neurons. Pre-incubation of primary neuronal Cultures with A beta peptides significantly inhibited NMDA-receptor function. albeit not by a direct pharmacological inhibition of NMDA-receptors, Since acute application of A beta peptides did not change NMDA-receptor Currents in autaptic hippocampal Cultures nor in xenopus oocytes expressing, recombinant NMDA-receptors. Pre-incubation of primary neuronal cultures with A beta peptides however decreased NR2B-immunoreactive synaptic spines and surface expression of NR2B containing NMDA-receptors. Furthermore. we extended these finding,, for the first time in vivo. demonstrating decreased concentrations of NMDA-receptor subunit NR2B and PSD-95 as well as activated alpha-CaMKII in postsynaptic density preparations of APP[V717I] transgenic mice. This was associated with impaired NMDA-dependent LTP and decreased NMDA- and AMPA-receptor currents in hippocampal CA1 region in APP[V717I] transgenic mice. In addition, induction of c-Fos following cued and contextual fear conditioning was significantly impaired in the basolateral amygdala and hippocampus of APP[V717I] transgenic mice. Our data demonstrate defects in NMDA-receptor function and learning dependent signaling cascades in vivo in APP[V717I] transgenic mice and point to decreased surface expression of NMDA-receptors as a mechanism involved in early synaptic defects in APP[V717I] transgenic mice in vivo. (C) 2007 Elsevier Inc. All rights reserved.