A large number of epidemiological studies have addressed the possible protective effect of antiinflammatory drug use with regard to Alzheimer's disease (AD) (McGeer et al., 1996). The most convincing of these studies— the Baltimore Longitudinal Study of Aging—utilized data collected prospectively, thereby minimizing recall bias issues. Corroborated by related studies, their results indicated a protective effect from the use of non-steroidal antiinflammatory drugs (NSAIDs) (Stewart et al., 1997). Available intervention studies support the beneficial efficacy of NSAIDs in AD. One small controlled trial of the NSAID indomethacin suggested that the drug slowed cognitive deterioration (Rogers et al., 1993). Recently, a small controlled trial of diclofenac showed similar results (although not statistically significant because of a high drop-out rate) (Scharf et al., 1999).
Evidence indicates that inflammatory mechanisms are activated in AD. For example, it has been found that amyloid plaques are surrounded by reactive microglia (as well as astrocytes), which have the characteristics of antigen-presenting tissue macrophages, including HLA-DR surface markers. In addition, there is clear evidence of an acute phase response (Vandenabeele et al., 1991), with upregulation of inflammatory cytokines, such as IL-1 and IL-6, and tumor necrosis factor (TNF)a, accompanied by an increase in acute phase proteins, such as a1-antichymotrypsin (ACT) and a2 macroglobulin (a2M). Further, there is an active complement system in the AD brain (Pasinetti, 1996) with generation of the lytic membrane attack complex (Webster et al., 1997) and, presumably, with release of anaphylatoxins. Our previous finding (Oda et al., 1995), showing that complement components potentiate amyloid neurotoxicity in vitro, is consistent with the evidence that overexpression of the inflammatory cytokine IL-6 in the brain leads to neurodegeneration (Campbell et al., 1993). Finally, upregulation of cyclooxygenase (COX)-2, but not COX-1, in AD neurons (Pasinetti et al., 1998) suggests that inflammatory lipids may also be involved in the pathogenesis of the disease (Pasinetti et al., 1998). However, it remains uncertain whether the inflammatory mechanisms actually cause damage in AD or are merely present to remove the debris of the neurodegenerative events (Aisen, 1997; Pasinetti, 1998).
In this chapter, new research directions, which address possible contributions of COX to AD neurodegeneration, are outlined. In particular, recent evidence is discussed, suggesting that neuronal COX-2 in the brain might influence neurodegeneration by promoting abortive attempts to re-enter the cell cycle. In addition, potential interventions are discussed, designed to control mechanisms in neurodegeneration in which COX is implicated. These considerations are critical to the understanding of the role of inflammation in the clinical progression of AD.
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