15 Oct 2001

Chronically elevated levels of cyclooxygenase-2 (COX-2), which catalyzes the first step in the synthesis of prostaglandins from arachidonic acid, have been correlated with induction of neuronal apoptosis, suggesting this enzyme may play a role in neurodegenerative disorders. This hypothesis is supported by the observation that non-steroidal anti-inflammatory drugs (NSAIDs), which target COX-2, are useful in preventing Alzheimer's disease. Further support comes from a report in today's Journal of Neuroscience that transgenic mice overexpressing human COX-2 in neurons exhibit age-dependent neuronal apoptosis accompanied by spatial memory deficits.

Katrin Andreasson at John's Hopkins University School of Medicine in Baltimore, Maryland, and colleagues subjected these mice to a battery of behavioral tests. As in wildtype controls, the ability of transgenics to remember the location of a submerged platform decreased with age. However, transgenic mice were statistically less adept at this task even though they were able to swim about as quickly as similarly aged controls. The researchers used two distinct tests to differentiate between the effects of age and memory loss on performance; the transgenic mice consistently scored worse on memory tests. 20-month-old transgenics were also slower at learning to avoid a shock stimulus than 12-month-old littermates, an age-dependent decline not seen among controls.

Transgenic animals had increased levels of glial fibrillary acid protein compared with controls, suggesting hCOX-2 leads to a greater activation of astrocytes. The number of apoptotic neurons was also significantly higher in the neocortex of the mutant animals.

"The strength of this paper is that it makes a clear connection between COX-2, behavior, and apoptosis," said Constantino Iadecola, professor of neurology at University of Minnesota, who reported earlier this year that mice deficient in COX-2 are protected from ischemia-induced glutamate excitotocity and resulting brain injury (Iadecola C et al.)—Tom Fagan