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Cyclooxygenase (COX)-2 and COX-1 potentiate beta-amyloid peptide generation through mechanisms that involve gamma-secretase activity.
J Biol Chem. 2003 Dec 19; 278(51):50970-7.JB

Abstract

In previous studies we found that overexpression of the inducible form of cyclooxygenase, COX-2, in the brain exacerbated beta-amyloid (A beta) neuropathology in a transgenic mouse model of Alzheimer's disease. To explore the mechanism through which COX may influence A beta amyloidosis, we used an adenoviral gene transfer system to study the effects of human (h)COX-1 and hCOX-2 isoform expression on A beta 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 approximately 1.8-fold elevation of A beta-(1-40) and A beta-(1-42) peptide generation and an approximately 1.8-fold induction of the C-terminal fragment (CTF)-gamma cleavage product of the APP, an index of gamma-secretase activity. Treatment of APP-overexpressing cells with the non-selective COX inhibitor ibuprofen (1 microM, 48 h) or with the specific gamma-secretase inhibitor L-685,458 significantly attenuated hCOX-1- and hCOX-2-mediated induction of A beta peptide generation and CTF-gamma cleavage product formation. Based on this evidence, we next tested the hypothesis that COX expression might promote A beta 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 (approximately 1.8-fold) the generation of the CTF-gamma cleavage product of APP and commensurate A beta-(1-40) and A beta-(1-42) peptide elevation. The study suggests that expression of COXs may influence A beta peptide generation through mechanisms that involve PG-E2-mediated potentiation of gamma-secretase activity, further supporting a role for COX-2 and COX-1 in Alzheimer's disease neuropathology.

Authors+Show Affiliations

Neuroinflammation Research Laboratories, Mount Sinai School of Medicine, New York, New York 10029, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

14507922

Citation

Qin, Weiping, et al. "Cyclooxygenase (COX)-2 and COX-1 Potentiate Beta-amyloid Peptide Generation Through Mechanisms That Involve Gamma-secretase Activity." The Journal of Biological Chemistry, vol. 278, no. 51, 2003, pp. 50970-7.
Qin W, Ho L, Pompl PN, et al. Cyclooxygenase (COX)-2 and COX-1 potentiate beta-amyloid peptide generation through mechanisms that involve gamma-secretase activity. J Biol Chem. 2003;278(51):50970-7.
Qin, W., Ho, L., Pompl, P. N., Peng, Y., Zhao, Z., Xiang, Z., Robakis, N. K., Shioi, J., Suh, J., & Pasinetti, G. M. (2003). Cyclooxygenase (COX)-2 and COX-1 potentiate beta-amyloid peptide generation through mechanisms that involve gamma-secretase activity. The Journal of Biological Chemistry, 278(51), 50970-7.
Qin W, et al. Cyclooxygenase (COX)-2 and COX-1 Potentiate Beta-amyloid Peptide Generation Through Mechanisms That Involve Gamma-secretase Activity. J Biol Chem. 2003 Dec 19;278(51):50970-7. PubMed PMID: 14507922.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Cyclooxygenase (COX)-2 and COX-1 potentiate beta-amyloid peptide generation through mechanisms that involve gamma-secretase activity. AU - Qin,Weiping, AU - Ho,Lap, AU - Pompl,Patrick N, AU - Peng,Yuanzhen, AU - Zhao,Zhong, AU - Xiang,Zhongmin, AU - Robakis,Nikolaos K, AU - Shioi,Junichi, AU - Suh,Jason, AU - Pasinetti,Giulio Maria, Y1 - 2003/09/24/ PY - 2003/9/26/pubmed PY - 2004/1/31/medline PY - 2003/9/26/entrez SP - 50970 EP - 7 JF - The Journal of biological chemistry JO - J. Biol. Chem. VL - 278 IS - 51 N2 - In previous studies we found that overexpression of the inducible form of cyclooxygenase, COX-2, in the brain exacerbated beta-amyloid (A beta) neuropathology in a transgenic mouse model of Alzheimer's disease. To explore the mechanism through which COX may influence A beta amyloidosis, we used an adenoviral gene transfer system to study the effects of human (h)COX-1 and hCOX-2 isoform expression on A beta 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 approximately 1.8-fold elevation of A beta-(1-40) and A beta-(1-42) peptide generation and an approximately 1.8-fold induction of the C-terminal fragment (CTF)-gamma cleavage product of the APP, an index of gamma-secretase activity. Treatment of APP-overexpressing cells with the non-selective COX inhibitor ibuprofen (1 microM, 48 h) or with the specific gamma-secretase inhibitor L-685,458 significantly attenuated hCOX-1- and hCOX-2-mediated induction of A beta peptide generation and CTF-gamma cleavage product formation. Based on this evidence, we next tested the hypothesis that COX expression might promote A beta 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 (approximately 1.8-fold) the generation of the CTF-gamma cleavage product of APP and commensurate A beta-(1-40) and A beta-(1-42) peptide elevation. The study suggests that expression of COXs may influence A beta peptide generation through mechanisms that involve PG-E2-mediated potentiation of gamma-secretase activity, further supporting a role for COX-2 and COX-1 in Alzheimer's disease neuropathology. SN - 0021-9258 UR - https://www.unboundmedicine.com/medline/citation/14507922/Cyclooxygenase__COX__2_and_COX_1_potentiate_beta_amyloid_peptide_generation_through_mechanisms_that_involve_gamma_secretase_activity_ L2 - http://www.jbc.org/cgi/pmidlookup?view=long&pmid=14507922 DB - PRIME DP - Unbound Medicine ER -