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

J Neurosci. 2001 Oct 15;21(20):8198-209. doi: 10.1523/JNEUROSCI.21-20-08198.2001.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Aging / metabolism*
  • Animals
  • Apoptosis
  • Astrocytes / metabolism
  • Astrocytes / pathology
  • Avoidance Learning
  • Behavior, Animal
  • Blotting, Western
  • Brain / pathology
  • Cognition Disorders / complications
  • Cognition Disorders / pathology
  • Cognition Disorders / physiopathology*
  • Cyclooxygenase 2
  • Immunohistochemistry
  • In Situ Nick-End Labeling
  • Isoenzymes / genetics
  • Isoenzymes / metabolism*
  • Maze Learning
  • Memory Disorders / etiology
  • Memory Disorders / physiopathology
  • Mice
  • Mice, Transgenic
  • Motor Skills
  • Neurodegenerative Diseases / complications
  • Neurodegenerative Diseases / pathology
  • Neurodegenerative Diseases / physiopathology*
  • Neurons / enzymology*
  • Neurons / pathology
  • Prostaglandin-Endoperoxide Synthases / genetics
  • Prostaglandin-Endoperoxide Synthases / metabolism*
  • Prostaglandins / metabolism


  • Isoenzymes
  • Prostaglandins
  • Cyclooxygenase 2
  • Prostaglandin-Endoperoxide Synthases