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

Ann Neurol. 2011 Jan;69(1):34-46. doi: 10.1002/ana.22234. Epub 2010 Nov 17.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / enzymology
  • Alzheimer Disease / genetics
  • Alzheimer Disease / metabolism
  • Amyloid Precursor Protein Secretases / drug effects
  • Amyloid Precursor Protein Secretases / metabolism
  • Amyloid beta-Peptides / biosynthesis*
  • Amyloid beta-Peptides / drug effects*
  • Amyloid beta-Peptides / metabolism
  • Amyloid beta-Protein Precursor / genetics
  • Amyloid beta-Protein Precursor / 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
  • Hydroxyeicosatetraenoic Acids / metabolism
  • Immunoblotting / methods
  • Immunoblotting / statistics & numerical data
  • Leukotrienes / biosynthesis
  • Linoleic Acids
  • Lipoxygenase Inhibitors / metabolism
  • Lipoxygenase Inhibitors / pharmacology
  • Mice
  • Mutation / genetics
  • Neuroblastoma
  • Transcription Factors / metabolism
  • Transfection
  • Tumor Cells, Cultured
  • Up-Regulation / drug effects


  • 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