Elsevier

Neurobiology of Aging

Volume 34, Issue 6, June 2013, Pages 1549-1554
Neurobiology of Aging

Regular article
5-Lipoxygenase pharmacological blockade decreases tau phosphorylation in vivo: involvement of the cyclin-dependent kinase-5

https://doi.org/10.1016/j.neurobiolaging.2012.12.009Get rights and content

Abstract

The 5-lipoxygenase (5LO) enzyme is widely distributed within the central nervous system. Previous works showed that this protein is upregulated in Alzheimer's disease, and that its genetic absence results in a reduction of amyloid beta levels in Tg2576 mice. However, its contribution to tau pathology remains to be investigated. To this end we studied the effect of 5LO chronic pharmacologic inhibition on endogenous tau level and metabolism in the same mice. The phosphorylation of tau at S396 and S396/404 in the brains of mice receiving zileuton, a selective and specific 5LO inhibitor, was significantly reduced when compared with their controls, while there was no significant change of tau phosphorylation at S202/T205, T231/S235, and T181 epitopes. The 5LO-dependent reduction of tau phosphorylation resulted from a significant decrease in the level and activity of the cyclin-dependent kinase-5 but not other kinases. Our findings highlight the novel functional role that neuronal 5LO plays in modulating tau phosphorylation, and suggest that pharmacologic inhibition of 5LO could provide a novel therapeutic opportunity also for Alzheimer's disease-related tau pathology.

Introduction

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by 2 major pathologic hallmark lesions: extracellular accumulation of β-amyloid (Aβ) plaques and intracellular accumulation of insoluble microtubule-associated protein tau as neurofibrillary tangles (Querfurth and Laferla, 2010). Mutations in the tau gene have been linked to neurofibrillary tangle formation in several neurodegenerative diseases called tauopathies in which no Aβ deposits are detected (Iqbal et al., 2010; Mederios et al., 2011). However, no mutations have been found in the tau gene in AD, and the relationship between tau metabolic fate, amyloid deposition, and neurodegeneration is difficult to establish.

Recently, we showed that the enzyme 5-lipoxygenase (5LO) is a new active player in AD pathogenesis. Thus, its protein levels are significantly increased in AD postmortem brain tissues and its genetic absence or pharmacological blockade both result in a significant reduction in the Aβ levels and deposition in a transgenic mouse model of AD-like amyloidosis (i.e., Tg2576) mice (Chu and Praticò 2011a; Chu et al., 2012b; Firuzi et al., 2008).

Because recent evidence indicates, at least in AD animal models, a link between Aβ and tau pathology and suggests that Aβ accumulation can exacerbate tau pathology (Oddo et al., 2008; Robertson et al., 2007), we were interested to assess whether pharmacologic inhibition of 5LO activation would result in significant changes in tau levels and/or metabolism.

To this end, Tg2576 mice were chronically administered with zileuton, a selective 5LO inhibitor (Berger et al., 2007), and the effect on tau levels and metabolism assessed.

Section snippets

Mice and treatments

All animal procedures were approved by the Institutional Animal Care and Usage Committee, and in accordance with the National Institutes of Health guidelines. Female Tg2576 transgenic mice expressing human amyloid precursor protein (APP) with the Swedish mutation (K670N/M671L) were used in these studies. They were genotyped by polymerase chain reaction analysis using tail DNA and kept in a pathogen-free environment, on a 12-hour light/dark cycle and had access to food and water ad libitum.

Pharmacologic blockade of 5LO reduces brain tau phosphorylation

Starting at 7 months of age Tg2576 mice were randomized to receive zileuton (200 mg/L) or vehicle for 8 months, then sacrificed and the effect of the treatment on tau level and metabolism assessed.

At the end of the study we observed that compared with controls, mice receiving zileuton had no change in their brain levels of total tau (Fig. 1A and B). By contrast, we found that the same animals manifested a significant reduction in its phosphorylated forms at S396 and S396/S404 as recognized by

Discussion

In the present study we provide the first experimental evidence supporting the concept that 5LO pharmacologic blockade could be a novel therapeutic intervention in AD tauopathy by reducing the hyperphosphorylation status of endogenous tau in a mouse model of the disease.

A constant feature of AD brain pathology is the intracellular accumulation of insoluble microtubules associated protein tau in selected brain regions. This type of brain pathology is also present in other neurodegenerative

Disclosure statement

The authors have no conflict of interest to disclose in relation to the work described in the present report.

Appropriate institutional approval and procedures were used concerning animals used in the study presented.

Acknowledgements

This study was in part supported by US National Institutes of Health (NIH) grants AG033568 and NS071096.

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