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Open Access Research

Involvement of 5-lipoxygenase activating protein in the amyloidotic phenotype of an Alzheimer’s disease mouse model

Jin Chu and Domenico Praticò*

Author Affiliations

Center for Translational Medicine, Department of Pharmacology, Temple University School of Medicine, 3420 North Broad Street MRB, 706A, Philadelphia, PA, 19140, USA

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Journal of Neuroinflammation 2012, 9:127  doi:10.1186/1742-2094-9-127

Published: 14 June 2012

Abstract

Background

The 5-lipoxygenase enzyme is widely distributed within the central nervous system and its activity is regulated by the presence and availability of another protein, called 5-lipoxygenase activating protein. While previous works have shown that 5-lipoxygenase is involved in the pathogenesis of Alzheimer’s disease, no data are available on the role that 5-lipoxygenase activating protein plays in Alzheimer’s disease.

Methods

In the present paper, we studied the effect of pharmacologic inhibition of 5-lipoxygenase activating protein on the amyloidotic phenotype of Tg2576 mice.

Results

Amyloid β peptide (Aβ) deposition in the brains of mice receiving MK-591, a selective and specific 5-lipoxygenase activating protein inhibitor, was significantly reduced when compared with controls. This reduction was associated with a similar decrease in brain Aβ peptides levels. MK-591 treatment did not induce any change in the steady-state levels of amyloid-β precursor protein, β-site amyloid precursor protein cleaving enzyme 1 or disintegrin and metalloproteinase domain-containing protein 10. By contrast, it resulted in a significant reduction of the γ-secretase complex, at the protein and message level. Furthermore, in vitro studies confirmed that MK-591 prevents Aβ formation by modulating γ-secretase complex levels without affecting Notch signaling.

Conclusions

These data establish a novel functional role for 5-lipoxygenase activating protein in the pathogenesis of Alzheimer’s disease-like amyloidosis, and suggest that its pharmacological inhibition could provide a novel therapeutic opportunity for Alzheimer’s disease.

Keywords:
Alzheimer’s disease; Amyloid β; Amyloid beta precursor protein; Animal model; 5-lipoxygenase activating protein