Pharmacologic blockade of 5-lipoxygenase improves the amyloidotic phenotype of an Alzheimer's disease transgenic mouse model involvement of γ-secretase.

Abstract

The 5-lipoxygenase (5-LO) enzyme is widely distributed within the central nervous system. Previous works showed that this protein is up-regulated in Alzheimer's disease (AD) and that its genetic absence results in a reduction of amyloid β (Aβ) levels in Tg2576 mice. In the present study, we examined the effect of 5-LO pharmacological inhibition on the amyloidotic phenotype of these mice. Aβ deposition in the brains of mice receiving zileuton, a selective and specific 5-LO inhibitor, was significantly reduced when compared with control Tg2576 mice receiving vehicle. This reduction was associated with a similar decrease in brain Aβ peptides levels. Zileuton treatment did not induce any change in the steady state levels of amyloid-β precursor protein (APP), BACE1 or ADAM10. By contrast, it resulted in a significant reduction of presenilin 1 (PSEN1, alias PS1), nicastrin (NCSTN) , presenilin enhancer 2 homolog (PSNEN, alias, Pen-2), and anterior pharynx defective 1 (APH-1), the four components of the γ-secretase complex-at the protein and message level. Furthermore, in vitro studies confirmed that zileuton prevents Aβ formation by modulating γ-secretase complex levels without affecting Notch signaling. These data establish a functional role for 5-LO in the pathogenesis of AD-like amyloidosis, whereby it modulates the γ-secretase pathway. They suggest that pharmacological inhibition of 5-LO could provide a novel therapeutic opportunity for AD.

• Authors: Jin Chu, Domenico Praticò
• Journal: The American journal of pathology (Am J Pathol) Vol. 178 Issue 4 Pg. 1762-9 (Apr 2011) ISSN: 1525-2191 [Electronic] United States
• PMID: 21435457 (Publication Type: Journal Article)
• Copyright: Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Chemical References

• Amyloid
• Amyloid beta-Peptides
• Lipoxygenase Inhibitors
• Receptors, Notch
• Amyloid Precursor Protein Secretases
• zileuton
• Hydroxyurea

Topics

• Alzheimer Disease (drug therapy, genetics)
• Amyloid (chemistry)
• Amyloid Precursor Protein Secretases (metabolism)
• Amyloid beta-Peptides (metabolism)
• Animals
• Female
• Fibroblasts (metabolism)
• Humans
• Hydroxyurea (analogs & derivatives, pharmacology)
• Immunohistochemistry (methods)
• Lipoxygenase Inhibitors (pharmacology)
• Mice
• Mice, Transgenic
• Models, Biological
• Mutation
• Phenotype
• Receptors, Notch (metabolism)