Cyclooxygenase-1 null mice show reduced neuroinflammation in response to beta-amyloid.

Several independent epidemiological studies indicate that chronic use of non-steroidal anti-inflammatory drugs can reduce the risk of developing Alzheimer's disease (AD), supporting the inflammatory cascade hypothesis. Although the first clinical trial with indomethacin, a preferential cyclooxygenase (COX)-1 inhibitor, showed beneficial effects, subsequent large clinical trials, mostly using COX-2 inhibitors, failed to show any beneficial effect in AD patients with mild to severe cognitive impairment. These combined data suggest that either an early treatment is crucial to stop the mechanisms underlying the disease before the onset of the symptoms, or that preferential COX-1 inhibition, rather than COX-2, is beneficial. Therefore, a full understanding of the physiological, pathological, and/or neuroprotective role of COX isoforms may help to develop better therapeutic strategies for the prevention or treatment of AD. In this study, we examined the effect of COX-1 genetic deletion on the inflammatory response and neurodegeneration induced by beta-amyloid. beta-amyloid (Abeta(1-42)) was centrally injected in the lateral ventricle of COX-1-deficient (COX-1(-/-)) and their respective wild-type (WT) mice. In COX-1(-/-) mice, Abeta(1-42)-induced inflammatory response and neuronal damage were attenuated compared to WT mice, as shown by Fluoro-Jade B and nitrotyrosine staining. These results indicate that inhibition of COX-1 activity may be valid therapeutic strategy to reduce brain inflammatory response and neurodegeneration.