Cyclooxygenases and 5-lipoxygenase in Alzheimer's disease

Abstract

Typically, cyclooxygenases (COXs) and 5-lipoxygenase (5-LOX), enzymes that generate biologically active lipid molecules termed eicosanoids, are considered inflammatory. Hence, their putative role in Alzheimer's disease (AD) has been explored in the framework of possible inflammatory mechanisms of AD pathobiology. More recent data indicate that these enzymes and the biologically active lipid molecules they generate could influence the functioning of the central nervous system and the pathobiology of neurodegenerative disorders such as AD via mechanisms different from classical inflammation. These mechanisms include the cell-specific localization of COXs and 5-LOX in the brain, the type of lipid molecules generated by the activity of these enzymes, the type and the localization of receptors selective for a type of lipid molecule, and the putative interactions of the COXs and 5-LOX pathways with intracellular components relevant for AD such as the gamma-secretase complex. Considering the importance of these multiple and not necessarily inflammatory mechanisms may help us delineate the exact nature of the involvement of the brain COXs and 5-LOX in AD and would reinvigorate the search for novel targets for AD therapy.

Figure 1

Putative mechanisms linking 5-LOX and COX pathways to Alzheimer’s disease (AD). 5-LOX could influence AD by producing pro-inflammatory leukotrienes (LTB4 and CysLTs) and anti-inflammatory lipoxins (naturally occurring LHA4 and aspirin-triggered 15-epi-LXA4) and by an interaction with the gamma-secretase complex. Cyclooxygenases could influence AD by acting on arachidonic acid (AA) and producing PGH2 and PGE2 (see text for details).