Amyloid-β induces cyclooxygenase-2 and PGE2 release in human astrocytes in NF-κ B dependent manner.
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.
Blanco
Almudena
A
Laboratorio Inmuno-Biología Molecular, Hospital General Universitario Gregorio Marañón, Madrid, Spain.
Alvarez
Susana
S
Fresno
Manuel
M
Muñoz-Fernández
Maria Ángeles
MÁ
D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D001253:Astrocytes / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D015232:Dinoprostone / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006801:Humans; D008156:Luciferases / Q000235:genetics; D016328:NF-kappa B / Q000378:metabolism*; D009578:Nitrobenzenes / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology*; D011392:Proline / Q000031:analogs & derivatives / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D013859:Thiocarbamates / Q000494:pharmacology; D014162:Transfection / Q000379:methods
D016229:Amyloid beta-Peptides; D004791:Enzyme Inhibitors; D016328:NF-kappa B; D009578:Nitrobenzenes; D010446:Peptide Fragments; D012333:RNA, Messenger; D013449:Sulfonamides; D013859:Thiocarbamates; C075222:amyloid beta-protein (1-42); C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; C066229:prolinedithiocarbamate; D011392:Proline; D008156:Luciferases; D051546:Cyclooxygenase 2; D015232:Dinoprostone