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Overexpression of neuronal cyclooxygenase -2 promotes amyloid deposition in the brain of transgenic mice with Alzheimers disease type neuropathology



Overexpression of neuronal cyclooxygenase -2 promotes amyloid deposition in the brain of transgenic mice with Alzheimers disease type neuropathology



Society for Neuroscience Abstracts 27(2): 1728



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. In this study 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 type plaque pathology, were crossed with transgenic mice expressing human (h)COX-2 in neurons. At 24 months, but not 12 and 16 months of age, the APPswe/PS1-A246E/hCOX-2 triple-transgenic mice showed a >2 fold elevation of Abeta (6E10) immunopositive plaques in frontal cortex and hippocampal formation, compared to APPswe/PS1-A246E double-transgenics (P<0.05) The increased number of amyloid deposits in the brain of the APPswe/PS1-A246E/hCOX-2 was confirmed by Congo-red birefringence. Interestingly, the elevated amyloid burden in the brain of the APPswe/PS1-A246E/hCOX-2 triple-transgenics relative to APPswe/PS1-A246E double-transgenics coincided with a commensurate elevation of complement receptor (CR)-3 immunopositive microglia. The present study has important implications for understanding the role of COX-2 in AD and, possibly, the development of therapeutic anti-inflammatory strategies for AD.

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