Pharmacologic inhibition of 5-lipoxygenase improves memory, rescues synaptic dysfunction, and ameliorates tau pathology in a transgenic model of tauopathy

Previous studies support the novel hypothesis that 5-LO could play an active role in modulating tau metabolic pathways important for the development of tauopathy. To test this hypothesis the authors administered zileuton,a selective and orally available 5-LO inhibitor, to transgenic tau mice (htau) in which the mouse tau gene was replaced by the nonmutated human tau gene. Results found that, compared to the htau mice receiving placebo, the mice treated with zileuton manifested a significant improvement in cognition and memory associated with restoration of their hippocampal synaptic function. In addition, pharmacologic inhibition of 5-LO yielded significant decreases in tau phosphorylation, which was mediated by a cyclin-dependent kinase 5 (cdk5) mechanism. These findings support a functional and direct role for 5-LO in the development of tau pathologic phenotype in vivo. These findings provide important preclinical evidence that this protein is a viable potential pharmacologic target for the treatment of tauopathies.