Mechanism of membrane depolarization caused by the Alzheimer Aβ1-42 peptide
Mechanism of membrane depolarization caused by the Alzheimer Aβ1-42 peptide
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DOI：
10.1016/s0006-291x(02)00346-7
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发表时间：
2002-05-17
影响因子：
3.1
通讯作者：
Ingram, VM
中科院分区：
文献类型：
--
作者：
Blanchard, BJ;Thomas, VL;Ingram, VM
我们报告了一个新的观察结果，当预先孵育时，神经毒性阿尔茨海默肽Abeta1-42。以浓度依赖的方式在分化的人HNT神经细胞和啮齿动物PC12细胞中引起戏剧性和持久的膜去极化。这种现象涉及代谢性谷氨酸受体mGluR(1)的激活。β诱导的PC 12细胞膜去极化对mGluR(1)拮抗剂、百日咳和霍乱毒素敏感，表明特定的G蛋白参与其中。这种效应不同于已知的聚集的Abeta1-42导致钙内流的能力。由于mGluR(1)激动剂模拟Abeta效应，我们推断在这个细胞系统中，谷氨酸可以控制其靶神经元的膜电位，从而控制其兴奋性。我们认为，在阿尔茨海默病中，Abeta诱导的膜去极化导致受影响神经元的过度兴奋，是该疾病中β-淀粉样蛋白毒性和认知功能障碍的关键分子机制。(C)2002年埃尔塞维尔科学公司(美国)。版权所有。
We report a novel observation that the neurotoxic Alzheimer peptide Abeta1-42, when pre-incubated. causes a dramatic and lasting membrane depolarization in differentiated human hNT neuronal cells and in rodent PC12 cells in a concentration-dependent manner. This phenomenon involves activation of the metabotropic glutamate receptor, mGluR(1). Abeta-induced membrane depolarization in PC 12 cells is sensitive to mGluR(1) antagonists and to pertussis and cholera toxins, indicating the involvement of particular G-proteins. The effect is different from the known ability of aggregated Abeta1-42 to cause a calcium influx. Since mGluR(1) agonists mimic the Abeta effect, we deduce that in this cell system glutamate can control the membrane potential and thereby the excitability of its target neurons. We propose that Abeta-induced membrane depolarization described here leads in Alzheimer's disease to hyperexcitability of affected neurons and is a crucially important molecular mechanism for beta-amyloid toxicity and cognitive dysfunction in the disease. (C) 2002 Elsevier Science (USA). All rights reserved.