Amelioration of the Alzheimer's disease phenotype by absence of 12/15-lipoxygenase.

Abstract

BACKGROUND:

Alzheimer's disease (AD) is a chronic neurodegenerative disorder whose initiating events are not known. Increasing evidence suggests that oxidative stress and inflammation play a role in its pathogenesis. 12/15 Lipoxygenase (12/15LO) by oxidizing polyunsaturated fatty acids forms hydroperoxyacids, which are potent pro-oxidants and inflammatory mediators. Previously, we reported that this metabolic pathway is increased in AD.

METHODS:

Here we explore the effect of genetic deletion of 12/15LO on the AD-like phenotype of the tg2576 transgenic mice.

RESULTS:

Genetic absence of this enzyme results in a significant reduction in amyloid-β (Aβ) production and deposition and an improvement of cognitive deficits. In vivo and in vitro studies show that the effect of this enzymatic pathway on amyloidosis is mediated by modulation of Aβ precursor protein processing via the β secretase (BACE) proteolytic cascade, which ultimately results in altered formation of Aβ peptides.

CONCLUSIONS:

Our findings support the novel hypothesis that blockade of 12/15LO in the central nervous system by modulating BACE proteolytic pathway could be an effective therapy for prevention or treatment of AD.

• Authors: Hengxuan Yang, Jia-Min Zhuo, Jin Chu, Cinzia Chinnici, Domenico Praticò
• Journal: Biological psychiatry (Biol Psychiatry) Vol. 68 Issue 10 Pg. 922-9 (Nov 15 2010) ISSN: 1873-2402 [Electronic] United States
• PMID: 20570249 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2010 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Chemical References

• 12-15-lipoxygenase
• Amyloid beta-Peptides
• Amyloid beta-Protein Precursor
• Arachidonate 12-Lipoxygenase
• Arachidonate 15-Lipoxygenase
• Amyloid Precursor Protein Secretases

Topics

• Alzheimer Disease (genetics, metabolism)
• Amyloid Precursor Protein Secretases (metabolism)
• Amyloid beta-Peptides (metabolism)
• Amyloid beta-Protein Precursor (metabolism)
• Animals
• Arachidonate 12-Lipoxygenase (genetics, metabolism)
• Arachidonate 15-Lipoxygenase (genetics, metabolism)
• Brain (metabolism)
• Cell Line, Transformed
• Cognition Disorders (genetics)
• Disease Models, Animal
• Female
• Mice
• Mice, Knockout
• Mice, Transgenic
• Plaque, Amyloid (metabolism)
• Signal Transduction (genetics)