FLAP pharmacological blockade modulates metabolism of endogenous tau in vivo

J Chu,A Di Meco,E Lauretti,D Praticò

doi:10.1038/tp.2013.106

Abstract

FLAP (5-lipoxygenase-activating protein) is a protein widely distributed within the central nervous system whose function is to regulate the activation of the 5-Lipoxygenase enzyme. Although previous works show that pharmacological blockade of FLAP improve the amyloidotic phenotype of the Tg2576, its contribution to tau pathology remains to be investigated. In the present paper, we studied the effect of FLAP pharmacological inhibition on the metabolism of endogenous tau in these mice. Total tau levels in the brains of mice receiving MK-591, a selective and specific FLAP inhibitor, were not changed when compared with controls. By contrast, treated animals had a significant reduction of tau phosphorylation at specific sites: Ser396; Ser396/Ser404; and Thr 231/Ser 235. This reduction was associated with a significant decrease in the activity of glycogen synthase kinase-3 beta, but not other kinases. In addition, MK-591-treated mice had a significant increase in the post-synaptic density protein-95 and the dendritic protein microtubule-associated protein 2. These data establish a novel functional role for FLAP in the metabolism of tau, and together with its known Aβ modulatory effect they suggest that its pharmacological inhibition could represent a novel therapeutic opportunity for Alzheimer's disease.

Highlights

Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by two major pathological hallmark lesions: extracellular accumulation of β-amyloid (Aβ) plaques and intracellular accumulation of insoluble microtubule-associated protein tau as neurofibrillary tangles.[1]
At the end of the study, we observed that compared with controls, mice receiving MK-591 had no change in their brain levels of total endogenous tau (Figures 1a and b)
Samples were electrophoresed on 10% Bis–Tris gels or 3–8% Tris–acetate gel (Bio-Rad, Richmond, CA, USA), according to the molecular weight of the target molecule, transferred onto nitrocellulose membranes (Bio-Rad), and incubated with appropriate primary antibodies shown in the Table 1

Summary

Introduction

Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by two major pathological hallmark lesions: extracellular accumulation of β-amyloid (Aβ) plaques and intracellular accumulation of insoluble microtubule-associated protein tau as neurofibrillary tangles.[1]. We showed that the enzyme 5-Lipoxygenase (5LO) is a new active player in the neurobiology of AD.[3] This enzyme is abundantly present in the central nervous system, where its activity is regulated by the presence and availability of another protein, called 5LO-activating protein or FLAP.[4] From a biochemical point of view they form a functional complex whose integrity is necessary for the full 5LO enzymatic activity. A peculiar aspect of the 5LO-activating protein (FLAP)/5LO pathway is the fact that its expression levels are significantly increased in the CNS with aging, and that this increase is region-specific as it mainly manifests in the hippocampus, an area vulnerable to neurodegenerative insults. We have reported that FLAP selective pharmacological inhibition significantly reduces Aβ levels and deposition in the amyloid precursor protein (APP) transgenic mice.[5] no data are available on the effect that this therapeutic intervention has on endogenous tau levels and metabolism in the same AD-like mouse model

Methods

Results

Conclusion