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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Tumor necrosis factors α and β protect neurons against amyloid β-peptide toxicity: Evidence for involvement of a κB-binding factor and attenuation of peroxide and Ca~(2+) accumulation
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Tumor necrosis factors α and β protect neurons against amyloid β-peptide toxicity: Evidence for involvement of a κB-binding factor and attenuation of peroxide and Ca~(2+) accumulation

机译：肿瘤坏死因子α和β保护神经元免受淀粉样β肽毒性的影响：κB结合因子参与以及过氧化物和Ca〜（2+）积累减少的证据

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摘要

In Alzheimer disease (AD) the amyloid β-peptide (Aβ) accumulates in plaques in the brain. Aβ can be neurotoxic by a mechanism involving induction of reactive oxygen species (ROS) and elevation of intracellular free calcium levels ([Ca~(2+)]_i). In light of evidence for an inflammatory response in the brain in AD and reports of increased levels of tumor necrosis factor (TNF) in AD brain we tested the hypothesis that TNFs affect neuronal vulnerability to Aβ. Aβ-(25-35) and Aβ-(1-40) induced neuronal degeneration in a concentration- and time-dependent manner. Pretreatment of cultures for 24 hr with TNF-β or TNF-α resulted in significant attenuation of Aβ-induced neuronal degeneration. Accumulation of peroxides induced in neurons by A? was significantly attenuated in TNF-pretreated cultures, and TNFs protected neurons against iron toxicity, suggesting that TNFs induce antioxidant pathways. The [Ca~(2+)]_i response to glutamate (quantified by fura-2 imaging) was markedly potentiated in neurons exposed to Aβ, and this action of Aβ was suppressed in cultures pretreated with TNFs. Electrophoretic mobility-shift assays demonstrated an induction of a κB-binding activity in hippocampal cells exposed to TNFs. Exposure of cultures to IκB (MAD3) antisense oligonucleotides, a manipulation designed to induce NF-κB, mimicked the protection by TNFs. These data suggest that TNFs protect hippocampal neurons against Aβ toxicity by suppressing accumulation of ROS and Ca~(2+) and that κB-dependent transcription is sufficient to mediate these effects. A modulatory role for TNF in the neurodegenerative process in AD is proposed.
机译：在阿尔茨海默氏病（AD）中，淀粉样β肽（Aβ）积聚在大脑斑块中。 Aβ可以通过涉及诱导活性氧（ROS）和升高细胞内游离钙水平（[Ca〜（2 +）] _ i）的机制而具有神经毒性。根据有关AD中大脑炎症反应的证据以及AD脑中肿瘤坏死因子（TNF）水平升高的报道，我们测试了TNF影响神经元对Aβ脆弱性的假说。 Aβ-（25-35）和Aβ-（1-40）以浓度和时间依赖性方式诱导神经元变性。用TNF-β或TNF-α预处理培养物24小时可显着减弱Aβ诱导的神经元变性。 Aβ诱导神经元中过氧化物的积累在TNF预处理的培养物中，TNF-α明显减弱，并且TNF保护神经元免受铁毒性，表明TNF诱导抗氧化途径。在暴露于Aβ的神经元中，对谷氨酸的[Ca〜（2 +）] _ i反应（通过fura-2成像量化）显着增强，在用TNF预处理的培养物中，Aβ的这种作用被抑制。电泳迁移率迁移分析证明了暴露于TNF的海马细胞中κB结合活性的诱导。将培养物暴露于IκB（MAD3）反义寡核苷酸（一种旨在诱导NF-κB的操作），类似于TNF的保护作用。这些数据表明，TNF通过抑制ROS和Ca〜（2+）的积累来保护海马神经元免受Aβ毒性，并且依赖κB的转录足以介导这些作用。提出了TNF在AD的神经变性过程中的调节作用。

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