Bibliographic
5-Lipoxygenase (5LO) is an enzyme that catalyzes the conversion of arachidonic acid to 5-hydroxy-peroxy-eicosatetraenoic acid (5-HPETE) and subsequently to hydroxyl-eicotetraenoic acid (5-HETE), which can be then metabolized in different leukotrienes. It is widely expressed in the neuronal cells of the central nervous system, where its level increases in an age-dependent manner in the hippocampus and cortex, two brain regions prone to neurodegenerative insult. Previous work have shown that this pathway is up-regulated in AD patients, and that its genetic absence or over-expression modulates Aβ levels and tau metabolism in transgenic mouse models of the disease. Recent studies show that treatment with an orally available and specific inhibitor of 5LO, zileuton, at an early stage of the development of the AD- like phenotype delays cognition impairments, reduces amyloid beta (Aβ) levels, and tau phosphorylation in the same mouse models of AD. The goal of this study was to test the efficacy and disease modifying properties of zileuton on behavioral and neuropathological hallmarks of late-stage AD. To this end the authors investigated the effect of zileuton on the late-stage, AD-like phenotype of the 3xTg mouse model. In this study, 12 month old 3xTg mice were dosed for 3 months with zileuton, or placebo. The data indicate that zileuton restores behavioral and cognitive function, significantly reduces Abeta deposition and tau hyperphosphorylation. In addition the data show that zileuton-mediated reduction in Abeta deposition and decreased tau phosphorylation are secondary to a gamma-secretase down regulation, and a decrease in the activation of CDK-5, respectively. The study provides further insights on the efficacy of 5LO pharmacologic inhibition as viable therapeutic approach for AD patients since it demonstrates that it has the potential to reverse all three of the most important aspects of the disease phenotype: memory decline, amyloid burden, and neurofibrillary tangles, after they are established.