title: Transcriptional regulation of β-secretase-1 by 12/15-lipoxygenase results in enhanced amyloidogenesis and cognitive impairments.
abstract: OBJECTIVE
  12/15-Lipoxygenase (12/15-LO) is an enzyme widely distributed in the central nervous system, and it has been involved in the neurobiology of Alzheimer disease (AD). However, the mechanism involved remains elusive.
  
  
  METHODS
  We investigated the molecular mechanism by which 12/15-LO regulates amyloid β (Aβ)/Aβ precursor protein (APP) metabolism in vivo and in vitro by genetic and pharmacologic approaches.
  
  
  RESULTS
  Here we show that overexpression of 12/15-LO leads to increased levels of β-secretase-1 (BACE1) mRNA and protein, a significant elevation in Aβ levels and deposition, and a worsening of memory deficits in AD transgenic mice. In vitro and in vivo studies demonstrate that 12/15-LO regulates BACE1 mRNA expression levels via the activation of the transcription factor Sp1. Thus, 12/15-LO-overexpressing mice had elevated levels of Sp1 and BACE1, whereas 12/15-LO-deficient mice had reduced levels of both. Preventing Sp1 activation by pharmacologic inhibition or dominant-negative mutant blocks the 12/15-LO-dependent elevation of Aβ and BACE1 levels.
  
  
  CONCLUSIONS
  Our findings demonstrate a novel pathway by which 12/15-LO increases the amyloidogenic processing of APP through a Sp1-mediated transcriptional control of BACE1 levels that could have implications for AD pathogenesis and therapy.
authors.affiliation: Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Jin
authors.initials: J
authors.lastname: Chu
authors.forename: Jia-Min
authors.initials: JM
authors.lastname: Zhuo
authors.forename: Domenico
authors.initials: D
authors.lastname: Praticò
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001092:Arachidonate 12-Lipoxygenase / Q000502:physiology*; D001093:Arachidonate 15-Lipoxygenase / Q000502:physiology*; D016282:Aspartic Acid Endopeptidases / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D003072:Cognition Disorders / Q000201:enzymology* / Q000235:genetics; D005260:Female; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D058225:Plaque, Amyloid / Q000201:enzymology* / Q000235:genetics; D011897:Random Allocation; D014158:Transcription, Genetic / Q000502:physiology*
chemical_list: C475064:12-15-lipoxygenase; D001092:Arachidonate 12-Lipoxygenase; D001093:Arachidonate 15-Lipoxygenase; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse