Amyloid-β Induces Cyclooxygenase-2 and PGE 2 Release in Human Astrocytes in NF-κ B Dependent Manner

Both amyloid-β peptide 1–42 (Aβ_1–42) 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 Aβ_1–42 and COX-2 is unclear. We found that the addition of Aβ_1–42 to astrocytoma cultures induced COX-2 mRNA and protein and PGE₂ synthesis in primary human astrocytes and in human astrocytoma cell lines. Moreover, Aβ_1–42 induced COX-2 promoter transcription. Deletion of nuclear factor-κB (NF-κB) sites of the promoter diminished Aβ_1–42-COX-2 dependent transcription. In agreement with this, Aβ_1–42 induced transcription of NF-κB reporter gene. In contrast, Aβ_1–42 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 Aβ_1–42. Over expression of NF-κB inhibitory subunit, IκB, completely abrogated Aβ_1–42-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, Aβ_1–42 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 Aβ_1–42 was corroborated by using the pharmacological inhibitor of the NF-κB pathway, PDTC. In addition, Aβ_1–42 treated astrocytoma supernatants were toxic for neuroblastoma cells, an effect which was blocked by PDTC. Summing up, our results indicate that Aβ_1–42 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.