Akama K T, Albanese C, Pestell R G, Van Eldik L J
Department of Cell and Molecular Biology, Northwestern University Medical School, Chicago, IL 60611-3008, USA.
Proc Natl Acad Sci U S A. 1998 May 12;95(10):5795-800. doi: 10.1073/pnas.95.10.5795.
The major pathological features of Alzheimer's disease (AD) include amyloid plaques composed primarily of the beta-amyloid (Abeta) peptide, degenerating neurons and neurofibrillary tangles, and the presence of numerous activated astrocytes and microglia. Although extensive genetic data implicate Abeta 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. Abeta 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 Abeta-induced molecular pathways mediating these responses in activated glia. We report that Abeta stimulates the activation of the transcription factor NFkappaB in rat astrocytes, that NFkappaB activation occurs selectively from p65 transactivation domain 2, and that Abeta-induced NO synthase expression and NO production occur through an NFkappaB-dependent mechanism. This demonstration of how Abeta couples an intracellular signal transduction pathway involving NFkappaB to a potentially neurotoxic response provides a key mechanistic link between Abeta and the generation of oxidative damage. Our results also suggest possible molecular targets upon which to focus future drug discovery efforts for AD.
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）肽组成的淀粉样斑块、神经元退变和神经原纤维缠结，以及大量活化的星形胶质细胞和小胶质细胞的存在。尽管大量遗传学数据表明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产生影响的分子机制以及神经胶质细胞活化与神经元死亡之间的关系仍未明确。已有研究表明Aβ可诱导神经胶质细胞活化，越来越多的证据表明活化的神经胶质细胞通过产生炎性细胞因子和神经毒性自由基（如一氧化氮（NO），已知其为AD中发生的氧化应激的重要来源）导致神经毒性。因此，识别Aβ诱导的、介导活化神经胶质细胞中这些反应的特定分子途径至关重要。我们报告，Aβ可刺激大鼠星形胶质细胞中转录因子NFκB的活化，NFκB的活化选择性地发生于p65反式激活结构域2，并且Aβ诱导的一氧化氮合酶表达和NO生成通过一种NFκB依赖性机制发生。这种关于Aβ如何将涉及NFκB的细胞内信号转导途径与潜在的神经毒性反应相联系的证明，为Aβ与氧化损伤产生之间提供了关键的机制联系。我们的结果还提示了未来AD药物研发可能聚焦的分子靶点。
