5-lipoxygenase as an endogenous modulator of amyloid β formation in vivo.

Abstract

OBJECTIVE:

The 5-lipoxygenase (5-LO) enzymatic pathway is widely distributed within the central nervous system, and is upregulated in Alzheimer's disease. However, the mechanism whereby it may influence the disease pathogenesis remains elusive.

METHODS:

We evaluated the molecular mechanism by which 5-LO regulates amyloid β (Aβ) formation in vitro and in vivo by pharmacological and genetic approaches.

RESULTS:

Here we show that 5-LO regulates the formation of Aβ by activating the cAMP-response element binding protein (CREB), which in turn increases transcription of the γ-secretase complex. Preventing CREB activation by pharmacologic inhibition or dominant negative mutants blocks the 5-LO-dependent elevation of Aβ formation and the increase of γ-secretase mRNA and protein levels. Moreover, 5-LO targeted gene disruption or its in vivo selective pharmacological inhibition results in a significant reduction of Aβ, CREB and γ-secretase levels.

INTERPRETATION:

These data establish a novel functional role for 5-LO in regulating endogenous formation of Aβ levels in the central nervous system. Thus, 5-LO pharmacological inhibition may be beneficial in the treatment and prevention of Alzheimer's disease.

• Authors: Jin Chu, Domenico Praticò
• Journal: Annals of neurology (Ann Neurol) Vol. 69 Issue 1 Pg. 34-46 (Jan 2011) ISSN: 1531-8249 [Electronic] United States
• PMID: 21280074 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2010 American Neurological Association.

Chemical References

• APP protein, human
• Amyloid beta-Peptides
• Amyloid beta-Protein Precursor
• CREB1 protein, human
• Chemotactic Factors
• Cyclic AMP Response Element-Binding Protein
• Hydroxyeicosatetraenoic Acids
• Leukotrienes
• Linoleic Acids
• Lipoxygenase Inhibitors
• Transcription Factors
• 5-hydroxy-6,8,11,14-eicosatetraenoic acid
• 13-hydroxy-9,11-octadecadienoic acid
• arachidonic acid 5-hydroperoxide
• Arachidonate 5-Lipoxygenase
• Amyloid Precursor Protein Secretases

Topics

• Alzheimer Disease (enzymology, genetics, metabolism)
• Amyloid Precursor Protein Secretases (drug effects, metabolism)
• Amyloid beta-Peptides (biosynthesis, drug effects, metabolism)
• Amyloid beta-Protein Precursor (genetics, metabolism)
• Animals
• Arachidonate 5-Lipoxygenase (pharmacology)
• Central Nervous System (metabolism)
• Chemotactic Factors
• Cyclic AMP Response Element-Binding Protein (metabolism)
• Enzyme Activation (drug effects)
• Female
• Humans
• Hydroxyeicosatetraenoic Acids (biosynthesis, metabolism)
• Immunoblotting (methods, statistics & numerical data)
• Leukotrienes (biosynthesis)
• Linoleic Acids
• Lipoxygenase Inhibitors (metabolism, pharmacology)
• Mice
• Mutation (genetics)
• Neuroblastoma
• Transcription Factors (metabolism)
• Transfection
• Tumor Cells, Cultured
• Up-Regulation (drug effects)