title: 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.
  
  
  CONCLUSIONS
  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.affiliation: Department of Pharmacology, Temple University, Philadelphia, PA, USA.
authors.forename: Jin
authors.initials: J
authors.lastname: Chu
authors.forename: Domenico
authors.initials: D
authors.lastname: Praticò
mesh_terms: D000544:Alzheimer Disease / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000187:drug effects / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000096:biosynthesis* / Q000187:drug effects* / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000494:pharmacology*; D002490:Central Nervous System / Q000378:metabolism; D002630:Chemotactic Factors; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000096:biosynthesis / Q000378:metabolism; D015151:Immunoblotting / Q000379:methods / Q000706:statistics & numerical data; D015289:Leukotrienes / Q000096:biosynthesis; D008041:Linoleic Acids; D016859:Lipoxygenase Inhibitors / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D009154:Mutation / Q000235:genetics; D009447:Neuroblastoma; D014157:Transcription Factors / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C545487:APP protein, human; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; C115163:CREB1 protein, human; D002630:Chemotactic Factors; D017362:Cyclic AMP Response Element-Binding Protein; D006893:Hydroxyeicosatetraenoic Acids; D015289:Leukotrienes; D008041:Linoleic Acids; D016859:Lipoxygenase Inhibitors; D014157:Transcription Factors; C022022:5-hydroxy-6,8,11,14-eicosatetraenoic acid; C024348:13-hydroxy-9,11-octadecadienoic acid; C025348:arachidonic acid 5-hydroperoxide; D001094:Arachidonate 5-Lipoxygenase; D053829:Amyloid Precursor Protein Secretases