Cyclooxygenase (COX)-2 and COX-1 Potentiate β-Amyloid Peptide Generation through Mechanisms That Involve γ-Secretase Activity

• Published in: The Journal of biological chemistry 2003-12, Vol.278 (51), p.50970-50977
• Main Authors: Qin, Weiping, Ho, Lap, Pompl, Patrick N., Peng, Yuanzhen, Zhao, Zhong, Xiang, Zhongmin, Robakis, Nikolaos K., Shioi, Junichi, Suh, Jason, Pasinetti, Giulio Maria
• Format: Article
• Language: English
• Subjects: Alzheimer Disease - etiology; Amyloid beta-Peptides - biosynthesis; Amyloid Precursor Protein Secretases; Animals; Aspartic Acid Endopeptidases; Cell Line; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors - pharmacology; Dinoprostone - pharmacology; Endopeptidases - drug effects; Endopeptidases - metabolism; Humans; Ibuprofen - pharmacology; Isoenzymes - physiology; Membrane Proteins; Peptide Fragments - biosynthesis; Prostaglandin-Endoperoxide Synthases - physiology; Transfection
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M307699200

In previous studies we found that overexpression of the inducible form of cyclooxygenase, COX-2, in the brain exacerbated β-amyloid (Aβ) neuropathology in a transgenic mouse model of Alzheimer's disease. To explore the mechanism through which COX may influence Aβ amyloidosis, we used an adenoviral gene transfer system to study the effects of human (h)COX-1 and hCOX-2 isoform expression on Aβ peptide generation. We found that expression of hCOXs in human amyloid precursor protein (APP)-overexpressing (Chinese hamster ovary (CHO)-APPswe) cells or human neuroglioma (H4-APP751) cells resulting in 10-25 nm prostaglandin (PG)-E2 concentration in the conditioned medium coincided with an ∼1.8-fold elevation of Aβ-(1-40) and Aβ-(1-42) peptide generation and an ∼1.8-fold induction of the C-terminal fragment (CTF)-γ cleavage product of the APP, an index of γ-secretase activity. Treatment of APP-overexpressing cells with the non-selective COX inhibitor ibuprofen (1 μm, 48 h) or with the specific γ-secretase inhibitor L-685,458 significantly attenuated hCOX-1- and hCOX-2-mediated induction of Aβ peptide generation and CTF-γ cleavage product formation. Based on this evidence, we next tested the hypothesis that COX expression might promote Aβ peptide generation via a PG-E2-mediated mechanism. We found that exposure of CHO-APPswe or human embryonic kidney (HEK-APPswe) cells to PG-E2 (11-deoxy-PG-E2) at a concentration (10 nm) within the range of PG-E2 found in hCOX-expressing cells similarly promoted (∼1.8-fold) the generation of the CTF-γ cleavage product of APP and commensurate Aβ-(1-40) and Aβ-(1-42) peptide elevation. The study suggests that expression of COXs may influence Aβ peptide generation through mechanisms that involve PG-E2-mediated potentiation of γ-secretase activity, further supporting a role for COX-2 and COX-1 in Alzheimer's disease neuropathology.