Cyclooxygenase (COX)-2 and cell cycle activity in a transgenic mouse model of Alzheimer’s Disease neuropathology

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 overexpr...

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Published in:	Neurobiology of aging Vol. 23; no. 3; pp. 327 - 334
Main Authors:	Xiang, Zhongmin, Ho, Lap, Valdellon, Jennifer, Borchelt, David, Kelley, Kevin, Spielman, Lauren, Aisen, Paul S., Pasinetti, Giulio Maria
Format:	Journal Article
Language:	English
Published:	London Elsevier Inc 01-05-2002 Elsevier Science
Subjects:	Alzheimer Disease - enzymology Alzheimer Disease - genetics Alzheimer Disease - pathology Alzheimer’s disease Amyloid beta-Peptides - genetics Amyloid beta-Peptides - metabolism Amyloid beta-Peptides - toxicity Animals Biological and medical sciences Caspase 3 Caspases - genetics Caspases - metabolism Cell cycle Cell Cycle - genetics Cell Death - genetics Cells, Cultured Cyclooxygenase Cyclooxygenase 2 Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases Disease Models, Animal Gene Expression Regulation, Enzymologic Humans Inflammation Isoenzymes - biosynthesis Isoenzymes - genetics Isoenzymes - metabolism Medical sciences Membrane Proteins Mice Mice, Inbred C3H Mice, Inbred C57BL Mice, Transgenic Neurology Neurons - enzymology Neurons - pathology Peptide Fragments - genetics Peptide Fragments - metabolism Peptide Fragments - toxicity Prostaglandin-Endoperoxide Synthases - biosynthesis Prostaglandin-Endoperoxide Synthases - genetics Prostaglandin-Endoperoxide Synthases - metabolism Transgenes Cyclooxygenase Inflammation Alzheimer’s disease Cell cycle Animal model Prostaglandin-endoperoxide synthase Nervous system diseases Enzyme Alzheimer disease Rodentia Transgenic animal Cerebral disorder Vertebrata Mammalia Mouse Central nervous system disease Degenerative disease Oxidoreductases
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Summary:	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 β-amyloid (Aβ) 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.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23
ISSN:	0197-4580 1558-1497
DOI:	10.1016/S0197-4580(01)00282-2