Prolonged exposure of cortical neurons to oligomeric amyloid-β impairs NMDA receptor function via NADPH oxidase-mediated ROS production: protective effect of green tea (-)-epigallocatechin-3-gallate.
Prolonged exposure of cortical neurons to oligomeric amyloid-β impairs NMDA receptor function via NADPH oxidase-mediated ROS production: protective effect of green tea (-)-epigallocatechin-3-gallate.
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DOI：
10.1042/an20100025
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发表时间：
2011-02-08
期刊：
影响因子：
4.7
通讯作者：
Sun GY
中科院分区：
文献类型：
--
作者：
He Y;Cui J;Lee JC;Ding S;Chalimoniuk M;Simonyi A;Sun AY;Gu Z;Weisman GA;Wood WG;Sun GY
Aβ（淀粉样蛋白β-肽）的过量产生已被证明在AD（阿尔茨海默病）的发病机制中起重要作用。虽然还没有很好地理解，但已知Aβ的聚集会对神经元产生毒性。我们最近的研究表明，寡聚Aβ能够通过NMDA （n -甲基-d-天冬氨酸）依赖途径刺激神经元中ROS（活性氧）的产生。然而，神经元长时间暴露于聚集的Aβ是否与NMDA受体功能损伤有关尚未得到广泛的研究。在本研究中，我们发现初级皮质神经元长时间暴露于Aβ寡聚物会导致线粒体功能障碍，NMDA受体介导的Ca2+内流的衰减和NMDA诱导的花生四烯酸释放的抑制。线粒体功能障碍和低聚Aβ引起的NMDA受体活性降低与ROS产生增加有关。Gp91ds-tat是NADPH氧化酶的特异性肽抑制剂，而Mn(III)-四苯甲酸-卟啉氯是一种ROS清除剂，可以有效地消除a β诱导的ROS产生。此外，a β诱导的线粒体功能障碍、NMDA Ca2+内流损伤和ROS产生可以通过用EGCG[(−)-epigallocatechin-3-gallate]（绿茶的主要多酚成分）预处理神经元来预防。综上所述，这些结果支持了NADPH氧化酶介导的ROS产生在a β细胞毒性作用中的作用，并证明了EGCG和其他膳食多酚在延缓AD发病或延缓AD进展方面的治疗潜力。
Excessive production of Aβ (amyloid β-peptide) has been shown to play an important role in the pathogenesis of AD (Alzheimer's disease). Although not yet well understood, aggregation of Aβ is known to cause toxicity to neurons. Our recent study demonstrated the ability for oligomeric Aβ to stimulate the production of ROS (reactive oxygen species) in neurons through an NMDA (N-methyl-d-aspartate)-dependent pathway. However, whether prolonged exposure of neurons to aggregated Aβ is associated with impairment of NMDA receptor function has not been extensively investigated. In the present study, we show that prolonged exposure of primary cortical neurons to Aβ oligomers caused mitochondrial dysfunction, an attenuation of NMDA receptor-mediated Ca2+ influx and inhibition of NMDA-induced AA (arachidonic acid) release. Mitochondrial dysfunction and the decrease in NMDA receptor activity due to oligomeric Aβ are associated with an increase in ROS production. Gp91ds-tat, a specific peptide inhibitor of NADPH oxidase, and Mn(III)-tetrakis(4-benzoic acid)-porphyrin chloride, an ROS scavenger, effectively abrogated Aβ-induced ROS production. Furthermore, Aβ-induced mitochondrial dysfunction, impairment of NMDA Ca2+ influx and ROS production were prevented by pre-treatment of neurons with EGCG [(−)-epigallocatechin-3-gallate], a major polyphenolic component of green tea. Taken together, these results support a role for NADPH oxidase-mediated ROS production in the cytotoxic effects of Aβ, and demonstrate the therapeutic potential of EGCG and other dietary polyphenols in delaying onset or retarding the progression of AD.