Age-dependent cognitive deficits and neuronal apoptosis in cyclooxygenase-2 transgenic mice

The cyclooxygenases catalyze the rate-limiting step in the formation of pro staglandins from arachidonic acid and are the pharmacological targets of (N SAIDs). In brain, cyclooxygenase-2 (COX-2), the inducible isoform of cycloo xygenase, is selectively expressed in neurons of the cerebral cortex, hippo campus, and amygdala. As an immediate-early gene, COX-2 is dramatically and transiently induced in these neurons in response to NMDA receptor activati on. In models of acute excitotoxic neuronal injury, elevated and sustained levels of COX-2 have been shown to promote neuronal apoptosis, indicating t hat upregulated COX-2 activity is injurious to neurons. COX-2 may also cont ribute to the development of Alzheimer's disease, for which early administr ation of NSAIDs is protective against development of the disease. To test t he effect of constitutively elevated neuronal COX-2, transgenic mice were g enerated that overexpressed COX-2 in neurons and produced elevated levels o f prostaglandins in brain. In cross-sectional behavioral studies, COX-2 tra nsgenic 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 mon ths of age. These behavioral changes were associated with a parallel age-de pendent increase in neuronal apoptosis occurring at 14 and 22 months but no t at 8 months of age and astrocytic activation at 24 months of age. These f indings suggest that neuronal COX-2 may contribute to the pathophysiology o f age-related diseases such as Alzheimer's disease by promoting memory dysf unction, neuronal apoptosis, and astrocytic activation in an age-dependent manner.