The apparent protective effect of NSAIDs suggests that COX might be involved in neurodegenerative mechanisms. In view of the great interest in clinical trials of NSAIDs in AD, we have investigated the role of COX in neurodegeneration (reviewed in Pasinetti, 1998). Traditional NSAIDs are non-selective COX inhibitors; their beneficial effects derive from inhibiting COX-2 activity. COX-1 inhibition, however, is more likely to mediate gastrointestinal, renal and platelet toxicity. Thus, the use of newly developed highly selective COX-2 inhibitors holds promise for maintained efficacy with vastly reduced toxicity (Vane et al., 1995; Warner et al., 1999).
Studies of post-mortem AD, as well as large number of epidemiological and interventional studies point to an important role of COX-2 in the pathophysiology of AD. In particular, the surprising discovery that, in the human brain, COX-2 is expressed primarily in neurons (see below) may have important implications for the treatment of neurodegenerative disorders (Ho et al., 1999, 2001 in press). Moreover, the tremendous resources being devoted by industry and academia to the testing of antiinflammatory drugs for the treatment of AD attests to the growing consensus in favor of the inflammatory hypothesis of the disease (Aisen, 1997).
The potential neuroprotective role of NSAIDs in AD has generally been attributed to suppression of deleterious inflammatory activity. However, evidence from our laboratory indicates a novel role for COX-2 in neuronal death mechanisms other than inflammatory responses. For example, we found that COX-2 might influence cell cycle activities in a model of AD. We found that APPswe/PS1-A246E transgenic mice that develop AD-like neuropathology (Borchelt et al., 1997), when backcrossed with transgenics with neuronal overexpression of human (h)COX-2 (Kelly et al., 1999), show a sharp elevation of cortical neurons immunopositive for phosphorylated serine 795 (S795) retinoblastoma (pRb) tumor suppressor protein and active caspase-3 (Xiang et al., submitted), which are indices of Ap1-42-mediated apoptotic damage (Giovanni et al., 2000). The elevation of neuronal pRb in the neurons of APPswe/PS1-A246E/hCOX-2 triple transgenics was of particular interest, since pRb regulates cell proliferation by controlling progression through the restriction point within the G1 phase of the cell cycle (Sherr and Roberts, 1999). While this study provided support to the hypothesis that a principal pathway by which neuronal COX-2 in brain may influence neurodegeneration is by promoting neurons to re-enter the cell cycle (Raina et al., 2000), the data also suggested a novel rational basis for targeting neuronal COX-2 in AD.
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