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The Journal of Neuroscience, October 15, 2001, 21(20):8198-8209
Age-Dependent Cognitive Deficits and Neuronal Apoptosis in Cyclooxygenase-2 Transgenic Mice
Katrin I. Andreasson1, 2, Alena Savonenko4, Sveta Vidensky1, Joseph J. Goellner6, Yan Zhang6, Alex Shaffer6, Walter E. Kaufmann1, 3, Paul F. Worley1, 2, Peter Isakson5, and Alicja L. Markowska4 Departments of 1 Neurology and 2 Neuroscience, Johns Hopkins University School of Medicine, and 3 Departments of Pathology, Pediatrics, Psychiatry and Behavioral Sciences, and Radiology and Radiological Sciences, Johns Hopkins University School of Medicine and Kennedy Krieger Institute, Baltimore, Maryland 21205, 4 Department of Psychology, Johns Hopkins University, Baltimore, Maryland 21218, 5 Pharmacia Research and Development, Peapack, New Jersey 07977, and 6 Pharmacia Research, St. Louis, Missouri 63198
The cyclooxygenases catalyze the rate-limiting step in the formation of prostaglandins from arachidonic acid and are the pharmacological targets of (NSAIDs). In brain, cyclooxygenase-2 (COX-2), the inducible isoform of cyclooxygenase, is selectively expressed in neurons of the cerebral cortex, hippocampus, and amygdala. As an immediate-early gene, COX-2 is dramatically and transiently induced in these neurons in response to NMDA receptor activation. In models of acute excitotoxic neuronal injury, elevated and sustained levels of COX-2 have been shown to promote neuronal apoptosis, indicating that upregulated COX-2 activity is injurious to neurons. COX-2 may also contribute to the development of Alzheimer's disease, for which early administration of NSAIDs is protective against development of the disease. To test the effect of constitutively elevated neuronal COX-2, transgenic mice were generated that overexpressed COX-2 in neurons and produced elevated levels of prostaglandins in brain. In cross-sectional behavioral studies, COX-2 transgenic mice developed an age-dependent deficit in spatial memory at 12 and 20 months but not at 7 months and a deficit in aversive behavior at 20 months of age. These behavioral changes were associated with a parallel age-dependent increase in neuronal apoptosis occurring at 14 and 22 months but not at 8 months of age and astrocytic activation at 24 months of age. These findings suggest that neuronal COX-2 may contribute to the pathophysiology of age-related diseases such as Alzheimer's disease by promoting memory dysfunction, neuronal apoptosis, and astrocytic activation in an age-dependent manner.
Key words: transgenic mouse; COX-2; spatial memory; aversive behavior; TUNEL; GFAP
Copyright © 2001 Society for Neuroscience 0270-6474/01/21208198-12$05.00/0
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