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

Katrin I. Andreasson, Alena Savonenko, Sveta Vidensky, Joseph J. Goellner, Yan Zhang, Alex Shaffer, Walter E. Kaufmann, Paul F. Worley, Peter Isakson, Alicja L. Markowska

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)8198-8209
Number of pages12
JournalJournal of Neuroscience
Volume21
Issue number20
DOIs
StatePublished - Oct 15 2001

Keywords

  • Aversive behavior
  • COX-2
  • GFAP
  • Spatial memory
  • TUNEL
  • Transgenic mouse

ASJC Scopus subject areas

  • Neuroscience(all)

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