The influence of 5-lipoxygenase on Alzheimer's disease-related tau pathology: in vivo and in vitro evidence.

Abstract

BACKGROUND:

Intracellular 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.

METHODS:

Tg2576 mice overexpressing neuronal 5LO were generated and its contribution to endogenous tau levels and metabolism investigated.

RESULTS:

Although 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.

CONCLUSIONS:

This 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.

• Authors: Jin Chu, Jian-Guo Li, Carolina Ceballos-Diaz, Todd Golde, Domenico Praticò
• Journal: Biological psychiatry (Biol Psychiatry) Vol. 74 Issue 5 Pg. 321-8 (Sep 01 2013) ISSN: 1873-2402 [Electronic] United States
• PMID: 23352590 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2013 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Chemical References

• tau Proteins
• Arachidonate 5-Lipoxygenase

Topics

• Alzheimer Disease (enzymology, metabolism, pathology)
• Animals
• Arachidonate 5-Lipoxygenase (metabolism)
• Female
• Mice
• Mice, Transgenic
• Neurons (metabolism, pathology)
• Synapses (metabolism, pathology)
• tau Proteins (metabolism)