The NF-κB/Rel family of proteins mediates Aβ-induced neurotoxicity and glial activation
The NF-κB/Rel family of proteins mediates Aβ-induced neurotoxicity and glial activation
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DOI：
10.1016/s0169-328x(98)00066-7
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发表时间：
1998-06-01
期刊：
影响因子：
--
通讯作者：
Paul, SM
中科院分区：
文献类型：
--
作者：
Bales, KR;Du, YS;Paul, SM
β -淀粉样肽（A β）沉积在神经斑块中，这是阿尔茨海默病（AD）的特征。这些斑块周围发生明显的神经退行性变和胶质细胞活化，导致假设A β可能在AD相关的神经元丢失和炎症反应中起致因作用。本研究表明，A β诱导的胚胎大鼠皮质神经元毒性与神经元暴露于A β后仅6小时开始的核小体间DNA断裂有关。此外，在暴露于a β后，胎鼠皮质神经元中容易测量到的构成性nf - κ B活性以浓度和时间依赖性的方式下降，但nf - κ B mRNA或蛋白没有相应的减少（p65）。在暴露于A β的皮质神经元中，I κ B α蛋白和mRNA的上调可能是细胞质中nf - κ B保留的原因，导致观察到的活化nf - κ B减少。后一种观点得到了支持，即对I κ B α mRNA进行反义寡核苷酸预处理的皮质培养物具有神经保护作用。与皮质神经元相反，大鼠原代星形胶质细胞暴露于A β导致nf - κ B的浓度和时间依赖性激活，随后上调IL-1 β和IL-6。我们的数据表明，A β诱导的神经毒性和星形胶质细胞激活可能由NF-kappa B/Rel家族蛋白介导，因此NF-kappa B导向基因表达的改变可能有助于AD发生的神经退行性变和炎症反应。(C) 1998 Elsevier Science B.V.版权所有
The beta-amyloid peptide (A beta) is deposited in neuritic plaques which are characteristic features of Alzheimer's disease (AD). Prominent neurodegeneration and glial activation occurs around these plaques leading to the hypothesis that A beta may play a causative role in the neuronal loss and the inflammatory response associated with AD. Here we show that A beta-induced toxicity of cultured fetal rat cortical neurons is associated with internucleosomal DNA fragmentation beginning just 6 h after neurons are exposed to A beta. Additionally, constitutive NF-kappa B activity readily measured in fetal rat cortical neurons decreases in a concentration- and time-dependent fashion following exposure to A beta, but there is no corresponding decrease in NF-kappa B mRNA or protein (p65). An upregulation of both I kappa B alpha protein and mRNA which occurs in cortical neurons exposed to A beta may be responsible for retaining NF-kappa B in the cytoplasm accounting for the observed decrease in activated NF-kappa B. The latter is supported by the observation that pretreatment of cortical cultures with an antisense oligonucleotide to I kappa B alpha mRNA is neuroprotective. In contrast to cortical neurons, exposure of rat primary astroglial cultures to A beta results in a concentration- and time-dependent activation of NF-kappa B with subsequent upregulation of IL-1 beta and IL-6. Our data suggest that A beta-induced neurotoxicity as well as astrocyte activation may be medicated by the NF-kappa B/Rel family of proteins, and thus alterations in NF-kappa B-directed gene expression may contribute to both the neurodegeneration and inflammatory response which occur in AD. (C) 1998 Elsevier Science B.V. All rights reserved.