title: Cyclooxygenase (COX)-2 and cell cycle activity in a transgenic mouse model of Alzheimer's disease neuropathology.
abstract: Prior studies have shown that cyclooxygenase (COX)-2, an enzyme involved in inflammatory mechanisms as well as neuronal activities, is up-regulated in the Alzheimer's disease (AD) brain and may represent a therapeutic target for anti-inflammatory treatments. We report the effect of neuronal overexpression of human (h)COX-2 in a murine model of AD neuropathology. Transgenic mice expressing both the human amyloid precursor protein mutation (APPswe) and the human presenilin (PS1-A246E) mutation, with resultant AD plaque pathology, were crossed with transgenic mice expressing human (h)COX-2 in neurons. At 12 months of age, the APPswe/PS1-A246E/hCOX-2 triple-transgenic mice showed an elevation in the number of phosphorylated retinoblastoma (pRb) tumor suppressor protein and active caspase-3 immunopositive neurons, compared to double APPswe/PS1-A246E or single hCOX-2 transgenic controls. No detectable influence of neuronal hCOX-2 on AD neuropathology was found in the brain of APPswe/PS1-A246E/hCOX-2 triple-transgenic mice, compared to double APPswe/PS1-A246E. In vitro studies revealed that hCOX-2 overexpression in primary cortico-hippocampal neurons derived from the hCOX-2 transgenics accelerates beta-amyloid (Abeta)(1-42)-mediated apoptotic damage which was prevented by the cell cycle dependent (CDK) inhibitor, flavoperidol. The data indicates that COX-2 overexpression causes alteration of neuronal cell cycle in a murine model of AD neuropathology, and provides a rational basis for targeting neuronal COX-2 in therapeutic research aimed at slowing the clinical progression of AD.
authors.affiliation: Neuroinflammation Research Laboratories, Department of Psychiatry, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029, USA.
authors.forename: Zhongmin
authors.initials: Z
authors.lastname: Xiang
authors.forename: Lap
authors.initials: L
authors.lastname: Ho
authors.forename: Jennifer
authors.initials: J
authors.lastname: Valdellon
authors.forename: David
authors.initials: D
authors.lastname: Borchelt
authors.forename: Kevin
authors.initials: K
authors.lastname: Kelley
authors.forename: Lauren
authors.initials: L
authors.lastname: Spielman
authors.forename: Paul S
authors.initials: PS
authors.lastname: Aisen
authors.forename: Giulio Maria
authors.initials: GM
authors.lastname: Pasinetti
mesh_terms: D000544:Alzheimer Disease / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism / Q000633:toxicity; D000818:Animals; D053148:Caspase 3; D020169:Caspases / Q000235:genetics / Q000378:metabolism; D002453:Cell Cycle / Q000235:genetics*; D016923:Cell Death / Q000235:genetics; D002478:Cells, Cultured; D051546:Cyclooxygenase 2; D004195:Disease Models, Animal; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007527:Isoenzymes / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism*; D008565:Membrane Proteins; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000201:enzymology / Q000473:pathology; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism / Q000633:toxicity; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism*; D019076:Transgenes
chemical_list: D016229:Amyloid beta-Peptides; D007527:Isoenzymes; D008565:Membrane Proteins; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases