Aβ oligomers induce neuronal oxidative stress through an N-methyl-D-aspartate receptor-dependent mechanism that is blocked by the Alzheimer drug memantine
Aβ oligomers induce neuronal oxidative stress through an N-methyl-D-aspartate receptor-dependent mechanism that is blocked by the Alzheimer drug memantine
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DOI：
10.1074/jbc.m607483200
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发表时间：
2007-04-13
影响因子：
4.8
通讯作者：
Klein, William L.
中科院分区：
文献类型：
--
作者：
De Felice, Fernanda G.;Velasco, Pauline T.;Klein, William L.
氧化应激是阿尔茨海默病(AD)病理的一个主要方面。我们研究了氧化应激与Aβ寡聚体(也称为ADDLS)神经元结合的关系。已知ADDLS在AD患者的脑组织中积聚，被认为与AD的发病机制密切相关。通过海马神经元培养，我们发现ADDLS通过需要N-甲基-D-天冬氨酸受体(NMDA-R)激活的机制来刺激活性氧物种(ROS)的过度形成。NMDA-Rs的NR1亚单位胞外区的抗体减少了ADTL与神经元的结合，并完全阻断了ROS的形成。与NR1抗体对ADDL结合的立体抑制相一致的是，结合到洗涤剂提取的突触体膜上的ADDL与NMDA-R亚单位共免疫沉淀。NR1抗体不影响NMDA诱导的ROS形成，表明NMDA-Rs本身仍具有功能。美金刚是一种开放通道的NMDA-R拮抗剂，作为AD患者的记忆保存药物，与其他NMDA-R拮抗剂一样，它完全防止ADDR诱导的ROS形成。美金刚和抗NR1抗体也减弱了ADD1诱导的神经元内钙的快速增加，这是刺激ROS形成所必需的。这些结果表明，ADDLS与NMDA-R结合或与其紧密结合，通过NMDA-R依赖的钙通道触发神经元损伤。这种反应为美金刚的治疗作用提供了一种病理上的特异性机制，表明了ROS失调在ADT1诱导的认知损害中的作用，并支持ADDLS在AD发病机制中发挥核心作用的统一假说。
Oxidative stress is a major aspect of Alzheimer disease ( AD) pathology. We have investigated the relationship between oxidative stress and neuronal binding of A beta oligomers ( also known as ADDLs). ADDLs are known to accumulate in brain tissue of AD patients and are considered centrally related to pathogenesis. Using hippocampal neuronal cultures, we found that ADDLs stimulated excessive formation of reactive oxygen species ( ROS) through a mechanism requiring N-methyl-D-aspartate receptor ( NMDA-R) activation. ADDL binding to neurons was reduced and ROS formation was completely blocked by an antibody to the extracellular domain of the NR1 subunit of NMDA-Rs. In harmony with a steric inhibition of ADDL binding by NR1 antibodies, ADDLs that were bound to detergent-extracted synaptosomal membranes co-immunoprecipitated with NMDA-R subunits. The NR1 antibody did not affect ROS formation induced by NMDA, showing that NMDA-Rs themselves remained functional. Memantine, an open channel NMDA-R antagonist prescribed as a memory-preserving drug for AD patients, completely protected against ADDL-induced ROS formation, as did other NMDA-R antagonists. Memantine and the anti-NR1 antibody also attenuated a rapid ADDL-induced increase in intraneuronal calcium, which was essential for stimulated ROS formation. These results show that ADDLs bind to or in close proximity to NMDA-Rs, triggering neuronal damage through NMDA-R-dependent calcium flux. This response provides a pathologically specific mechanism for the therapeutic action of memantine, indicates a role for ROS dysregulation in ADDL-induced cognitive impairment, and supports the unifying hypothesis that ADDLs play a central role in AD pathogenesis.