Amyloid β-peptide stimulates nitric oxide production in astrocytes through an NFκB-dependent mechanism
Amyloid β-peptide stimulates nitric oxide production in astrocytes through an NFκB-dependent mechanism
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DOI：
10.1073/pnas.95.10.5795
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发表时间：
1998-05-12
影响因子：
11.1
通讯作者：
Van Eldik, LJ
中科院分区：
文献类型：
--
作者：
Akama, KT;Albanese, C;Van Eldik, LJ
阿尔茨海默病(AD)的主要病理特征包括主要由β-淀粉样蛋白(Aβ)组成的淀粉样斑块、变性神经元和神经原纤维缠结，以及大量激活的星形胶质细胞和小胶质细胞的存在，尽管广泛的遗传学数据表明Aβ参与了AD的神经退行性级联反应，但其对神经元和神经胶质细胞的影响的分子机制以及胶质细胞激活和神经元死亡之间的关系尚不清楚。已有研究表明，Aβ可诱导神经胶质细胞的激活，而且越来越多的证据表明，激活的神经胶质细胞通过产生炎症细胞因子和神经毒性自由基，如一氧化氮(NO)，这是已知在AD中发生的氧化应激的有效来源，从而导致神经毒性。因此，在激活的胶质细胞中确定Aβ诱导的介导这些反应的特定分子通路是至关重要的，我们报道了Aβ刺激大鼠星形胶质细胞中转录因子NF kappa B的激活，NF kappa B的激活选择性地发生在p65反式激活区域2，并且Aβ诱导的NO合成酶的表达和NO的产生是通过依赖于NF kappa B的机制发生的。AP如何将涉及核因子kappaB的细胞内信号转导通路耦合到潜在的神经毒性反应中，这一演示提供了Aβ和氧化损伤产生之间的关键机制联系。我们的结果还提示了可能的分子靶点，未来AD的药物发现工作将集中在这些靶点上。
The major pathological features of Alzheimer's disease (AD) include amyloid plaques composed primarily of the beta-amyloid (A beta) peptide, degenerating neurons and neurofibrillary tangles, and the presence of numerous activated astrocytes and microglia, Although extensive genetic data implicate A beta in the neurodegenerative cascade of AD, the molecular mechanisms underlying its effects on neurons and glia and the relationship between glial activation and neuronal death are not well defined. A beta has been shown to induce glial activation, and a growing body of evidence suggests that activated glia contribute to neurotoxicity through generation of inflammatory cytokines and neurotoxic free radicals, such as nitric oxide (NO), potent sources of oxidative stress known to occur in AD. It is therefore crucial to identify specific A beta-induced molecular pathways mediating these responses in activated glia, We report that A beta stimulates the activation of the transcription factor NF kappa B in rat astrocytes, that NF kappa B activation occurs selectively from p65 transactivation domain 2, and that A beta-induced NO synthase expression and NO production occur through an NF kappa B-dependent mechanism. This demonstration of how AP couples an intracellular signal transduction pathway involving NF kappa B to a potentially neurotoxic response provides a key mechanistic link between A beta and the generation of oxidative damage. Our results also suggest possible molecular targets upon which to focus future drug discovery efforts for AD.