The role of the 5-lipoxygenase pathway in Alzheimer's disease

Many neurological diseases are now recognized to involve neuroinflammation as a major pathological feature. Neuroinflammation can be both a cause and a consequence of the disease process in Alzheimer's disease (AD). Chronic use of nonsteroidal antiinflammatory drugs (NSAIDs) has been found to delay the onset of AD and slow disease progression, a finding that has stimulated substantial interest in the role of these drugs in the prevention and treatment of AD. Unfortunately, recent clinical trials involving NSAIDs either have produced negative results or have been suspended due to toxicity issues concerning cyclooxygenase inhibition (e.g., ADAPT). Consequently, there is an urgent need to develop and test new antiinflammatory drugs devoid of the toxic effects associated with cyclooxygenase inhibition but which still suppress neuroinflammation and beta-amyloid-induced neurotoxicity. In addition to the cyclooxygenase pathway, arachidonic acid is also metabolized by the lipoxygenase pathway to form leukotrienes and lipoxins. There is some evidence indicating that 5-lipoxygenase inhibitors may offer protection against various aspects of the pathogenesis of AD. Based on these findings, we suggest that 5-lipoxygenase inhibitors may have therapeutic potential in the prevention and treatment of AD.