α7 Nicotinic acetylcholine receptor as a target to rescue deficit in hippocampal UP induction in β-amyloid infused rats
α7 Nicotinic acetylcholine receptor as a target to rescue deficit in hippocampal UP induction in β-amyloid infused rats
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DOI：
10.1016/j.neuropharm.2005.09.018
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发表时间：
2006-02-01
影响因子：
4.7
通讯作者：
Sokabe, M
中科院分区：
文献类型：
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作者：
Chen, L;Yamada, K;Sokabe, M
在动物模型中持续脑室注射β-淀粉样多肽1-40(Aβ((1-40)可导致与胆碱能神经系统功能障碍相关的学习和记忆障碍，被认为是阿尔茨海默病的病理模型[Nitta，A.，Itch，A.，Hasegawa，T.，Nabeshima，T.，1994。β-淀粉样蛋白诱导的阿尔茨海默病动物模型。神经科。让我们来吧。170、63-66。]。在这里，利用实时光学记录技术，我们证明了在Aβ灌流脑的海马片的Schaffer侧支-CA1突触中，基础突触传递和几种形式的突触可塑性，包括长时程增强(LTP)、强直后增强(PTP)和双脉冲易化(PPF)都是缺乏的。在整个研究中，努力解决的是α7烟碱型乙酰胆碱受体(α7nAChR)，它被认为是Aβ的主要靶标[Wang，H.Y.，Lee，D.H.，Davis，C.B.，Shank，R.P.，2000a。淀粉样多肽Aβ(1-42)选择性地与α7烟碱型乙酰胆碱受体结合并具有皮摩尔亲和力。J·神经化学。75,1155-1161.]，是在注射Aβ的大鼠中观察到的突触可塑性缺陷的原因。首先，我们发现Aβ输注显著抑制α7nAChR对选择性a7nAChR激动剂[3-(2，4-二甲氧基亚甲基)-anabaseine](DMXB)的反应。第二，用甲基乌头碱(MLA)或α-银环蛇毒素(α-BTX)阻断对照组大鼠的α7nAChR可抑制LTP的诱导，提示LTP的诱导需要α7nAChR的激活。最后，用10 mU的DMXB对Aβ灌流的大鼠脑片进行预处理，使CA1突触从LTP和PPF的缺陷中恢复过来。这些结果表明，Aβ受损的LTP和PPF是α7nAChR功能障碍的结果，α7nAChR可能是帮助改善AD患者认知障碍的重要靶点。(C)2005爱思唯尔有限公司。保留所有权利。
Continuous intracerebroventricular infusion of beta-amyloid peptide 1-40 (A beta((1-40))) in animal models induces learning and memory impairment associated with dysfunction of the cholinergic neuronal system, which has been considered to be a pathological model of Alzheimer's disease [Nitta, A., Itch, A., Hasegawa, T., Nabeshima, T., 1994. beta-amyloid protein-induced Alzheimer's disease animal model. Neurosci. Lett. 170, 63-66.]. Here, using a real-time optical recording technique, we demonstrate that basal synaptic transmission and several forms of synaptic plasticity, including long-term potentiation (LTP), post-tetanic potentiation (PTP) and paired-pulse facilitation (PPF) are deficient at the Schaffer collateral-CA1 synapse in hippocampal slices from A beta-infused brain. Throughout this study, an effort was made to address whether the alpha 7 nicotinic acetylcholine receptor (alpha 7nAChR), which is believed to be a primary target of A beta [Wang, H.Y., Lee, D.H., Davis, C.B., Shank, R.P., 2000a. Amyloid peptide A beta (1-42) binds selectively and with picomolar affinity to alpha 7 nicotinic acetylcholine receptors. J. Neurochem. 75, 1155-1161.], is responsible for the deficits in synaptic plasticity observed in the A beta-infused rats. First, we found that A beta-infusion markedly depressed the response of alpha 7nAChR to a selective a7nAChR agonist [3-(2,4-dimethoxybenzylidene)-anabaseine] (DMXB). Second, blockade of alpha 7nAChR with either methyllycaconitine (MLA) or alpha-bungarotoxin (alpha-BTX) in control rats inhibited LTP induction, suggesting that the activation of alpha 7nAChR is required for LTP induction. Finally, pre-treatment of the slices from A beta-infused rats with 10 mu M DMXB rescued CA1 synapses from the deficit in LTP and PPF. These results suggest that A beta-impaired LTP and PPF arise as a consequence of dysfunctional alpha 7nAChR, and that alpha 7nAChR may be an important target to help ameliorate AD patient cognitive deficits. (c) 2005 Elsevier Ltd. All rights reserved.