5-Lipoxygenase gene disruption reduces amyloid-β pathology in a mouse model of Alzheimer's disease

5-Lipoxygenase (5LO), by producing leukotrienes, is a proinflammatory enzyme, and there is evidence suggesting that it is up-regulated with aging and may be involved in Alzheimer's disease (AD). In this paper, we studied the effect of 5LO-targeted gene disruption on the amyloid phenotype of a transgenic mouse model of AD, the Tg2576. Amyloid-beta (A beta) deposition in the brains of Tg2576 mice lacking 5LO was reduced by 64-80% compared with Tg2576 controls. This reduction was associated with a similar significant decrease in A beta levels measured by sandwich ELISA. Absence of 5LO did not induce any significant change in amyloid-beta precursor protein (APP) levels and processing, or A beta catabolic pathways. Furthermore, in vitro studies showed that 5LO activation or 5LO metabolites increase, whereas 5LO inhibition decreases, A beta formation, secondary to correspondent changes in gamma-secretase activity. These data establish for the first time a novel functional role for 5LO in the pathogenesis of AD-like amyloidosis, thereby modulating gamma-secretase activity. Our work suggests that pharmacological inhibition of 5LO could provide a novel therapeutic tool for AD.