Laboratorio Inmuno-Biología Molecular, Hospital General Universitario Gregorio Marañón, Madrid, Spain.
J Alzheimers Dis. 2010;22(2):493-505. doi: 10.3233/JAD-2010-100309.
Both amyloid-β peptide 1-42 (Aβ1-42) formation and cyclooxygenase-2 (COX-2) have been involved in the pathogenesis of Alzheimer's disease (AD), a devastating neurological disorder. However, the relationship between Aβ1-42 and COX-2 is unclear. We found that the addition of Aβ1-42 to astrocytoma cultures induced COX-2 mRNA and protein and PGE2 synthesis in primary human astrocytes and in human astrocytoma cell lines. Moreover, Aβ1-42 induced COX-2 promoter transcription. Deletion of nuclear factor-κB (NF-κB) sites of the promoter diminished Aβ1-42-COX-2 dependent transcription. In agreement with this, Aβ1-42 induced transcription of NF-κB reporter gene. In contrast, Aβ1-42 neither did not induce NFAT not AP-1 factors activation suggesting that both NFAT and AP-1 was not necessary to control COX-2 transcription induced by Aβ1-42. Over expression of NF-κB inhibitory subunit, IκB, completely abrogated Aβ1-42-induced COX-2 activity in U-87 cells, whereas the opposite effect was shown when p65/rel A NF-κB was over expressed. In addition, Aβ1-42 induced p65/rel A subunit translocation to the nucleus and binding to the distal site of the COX-2 promoter. The importance of NF-κB in COX-2 induction and PGE2 synthesis by Aβ1-42 was corroborated by using the pharmacological inhibitor of the NF-κB pathway, PDTC. In addition, Aβ1-42 treated astrocytoma supernatants were toxic for neuroblastoma cells, an effect which was blocked by PDTC. Summing up, our results indicate that Aβ1-42 was able to induce COX-2 and PGE2 synthesis in astrocytic cells through a NF-κB dependent mechanism. This may have implicated in our understanding of AD pathology.
淀粉样β肽 1-42（Aβ1-42）的形成和环氧化酶-2（COX-2）都与阿尔茨海默病（AD）的发病机制有关，AD 是一种破坏性的神经退行性疾病。然而，Aβ1-42 和 COX-2 之间的关系尚不清楚。我们发现，向星形细胞瘤培养物中添加 Aβ1-42 可诱导原代人星形胶质细胞和人星形细胞瘤细胞系中的 COX-2 mRNA 和蛋白以及 PGE2 合成。此外，Aβ1-42 诱导 COX-2 启动子转录。启动子中核因子-κB（NF-κB）位点的缺失减弱了 Aβ1-42-COX-2 依赖性转录。与此一致的是，Aβ1-42 诱导 NF-κB 报告基因的转录。相反，Aβ1-42 既不诱导 NFAT 也不诱导 AP-1 因子的激活，表明 NFAT 和 AP-1 均不是控制 Aβ1-42 诱导的 COX-2 转录所必需的。NF-κB 抑制亚基 IκB 的过表达完全阻断了 U-87 细胞中 Aβ1-42 诱导的 COX-2 活性，而当过表达 p65/rel A NF-κB 时则表现出相反的效果。此外，Aβ1-42 诱导 p65/rel A 亚基向核内易位并与 COX-2 启动子的远端位点结合。用 NF-κB 途径的药理学抑制剂 PDTC 证实了 NF-κB 在 Aβ1-42 诱导的 COX-2 诱导和 PGE2 合成中的重要性。此外，Aβ1-42 处理的星形细胞瘤上清液对神经母细胞瘤细胞有毒性，这种作用被 PDTC 阻断。总之，我们的结果表明，Aβ1-42 能够通过 NF-κB 依赖性机制诱导星形胶质细胞中 COX-2 和 PGE2 的合成。这可能有助于我们理解 AD 的病理学。
