The Influence of 5-Lipoxygenase on Alzheimer’s Disease-Related Tau Pathology: In Vivo and In Vitro Evidence

BackgroundIntracellular deposition of tau protein is a hallmark lesion of Alzheimer’s disease. Although it is known this event is secondary to excessive tau phosphorylation, the mechanisms involved remain unknown. We previously reported that the enzyme 5-Lipoxygenase (5LO) acts as a modulator of Aβ peptides formation in vivo, and here we investigate its influence on tau protein.MethodsTg2576 mice overexpressing neuronal 5LO were generated and its contribution to endogenous tau levels and metabolism investigated.ResultsAlthough no differences were noted in the levels of total tau for both groups, compared with controls, Tg2576 mice overexpressing 5LO had a significant increase in the phosphorylation state of tau at S396 and S396/S404, as recognized by the antibodies PHF-13 and PHF-1, respectively. By contrast, no phosphorylation changes were observed in other tau epitopes. This increase was associated with a significant elevation in cyclin dependent kinase-5 but not other kinases that have been involved in tau phosphorylation. Additionally, mice overexpressing 5LO had biochemical evidence of altered synaptic integrity because they manifested a reduction in PSD-95, synaptophysin and MAP2.ConclusionsThis study demonstrates a new role for 5LO in regulating endogenous tau metabolism in the central nervous system and supports the hypothesis that its pharmacologic inhibition could be beneficial for Alzheimer’s disease-related tau neuropathology.