A Novel Nicotinic Mechanism Underlies β-Amyloid-Induced Neuronal Hyperexcitation
A Novel Nicotinic Mechanism Underlies β-Amyloid-Induced Neuronal Hyperexcitation
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DOI：
10.1523/jneurosci.3235-12.2013
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发表时间：
2013-04-24
影响因子：
5.3
通讯作者：
Wu, Jie
中科院分区：
文献类型：
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作者：
Liu, Qiang;Xie, Xitao;Wu, Jie
在阿尔茨海默病（AD）中癫痫的发病率显著升高。此外，在表达异常水平或形式的淀粉样前体蛋白及其假定的致病产物淀粉样蛋白-β的转基因小鼠中存在神经过度兴奋/同步化（1）（42）（A β）。然而，A β如何引起神经元过度兴奋的潜在机制仍不清楚。在这里，我们报告说，暴露于病理相关水平的A β诱导A β形式依赖性，浓度依赖性和时间依赖性的神经元过度兴奋在原代培养的小鼠海马神经元。类似地，A β暴露增加细胞表面上的烟碱乙酰胆碱受体（nAChR）α 7亚基蛋白的水平和α 7-nAChR功能，但不增加α 7亚基mRNA，表明功能性α 7-nAChR的翻译后上调。这些作用在共暴露于布雷菲德菌素A（一种内质网至高尔基体蛋白转运的抑制剂）后被阻止，这与对α 7亚基和组装的α 7-nAChR向细胞表面的运输的作用一致。在神经元过度兴奋表达之前，β-肾上腺素诱导的α 7-nAChR功能上调发生。使用α 7-nAChR拮抗剂或nAChR α 7亚基基因缺失的药理学抑制可防止神经元过度兴奋的诱导和表达。总的来说，这些结果，在使用切片培养物的研究中得到证实，表明α 7-nAChR的功能活性和可能的功能上调对于产生A β诱导的神经元过度兴奋和可能的AD发病机制是必要的。这种涉及α 7-nAChR介导A β效应的新机制为治疗AD提供了潜在的新治疗靶点。
There is a significantly elevated incidence of epilepsy in Alzheimer's disease (AD). Moreover, there is neural hyperexcitation/synchronization in transgenic mice expressing abnormal levels or forms of amyloid precursor protein and its presumed, etiopathogenic product, amyloid-beta(1) (42) (A beta). However, the underlying mechanisms of how A beta causes neuronal hyperexcitation remain unclear. Here, we report that exposure to pathologically relevant levels of A beta induces A beta form-dependent, concentration-dependent, and time-dependent neuronal hyperexcitation in primary cultures of mouse hippocampal neurons. Similarly, A beta exposure increases levels of nicotinic acetylcholine receptor (nAChR) alpha 7 subunit protein on the cell surface and alpha 7-nAChR function, but not alpha 7 subunit mRNA, suggesting post-translational upregulation of functional alpha 7-nAChRs. These effects are prevented upon coexposure to brefeldin A, an inhibitor of endoplasmic reticulum-to-Golgi protein transport, consistent with an effect on trafficking of alpha 7 subunits and assembled alpha 7-nAChRs to the cell surface. A beta exposure-induced alpha 7-nAChR functional upregulation occurs before there is expression of neuronal hyperexcitation. Pharmacological inhibition using an alpha 7-nAChR antagonist or genetic deletion of nAChR alpha 7 subunits prevents induction and expression of neuronal hyperexcitation. Collectively, these results, confirmed in studies using slice cultures, indicate that functional activity and perhaps functional upregulation of alpha 7-nAChRs are necessary for production of A beta-induced neuronal hyperexcitation and possibly AD pathogenesis. This novel mechanism involving alpha 7-nAChRs in mediation of A beta effects provides potentially new therapeutic targets for treatment of AD.