title: 5-Lipoxygenase gene transfer worsens memory, amyloid, and tau brain pathologies in a mouse model of Alzheimer disease.
abstract: OBJECTIVE
  The 5-lipoxygenase (5LO) enzyme is upregulated in Alzheimer disease (AD), and its genetic absence reduces Aβ levels in APP mice. However, its functional role in modulating tau neuropathology remains to be elucidated.
  
  
  METHODS
  To this end, we generated triple transgenic mice (3xTg-AD) overexpressing neuronal 5LO and investigated their phenotype.
  
  
  RESULTS
  Compared with controls, 3xTg-AD mice overexpressing 5LO manifested an exacerbation of memory deficits, plaques, and tangle pathologies. The elevation in Aβ was secondary to an upregulation of γ-secretase pathway, whereas tau hyperphosphorylation resulted from an activation of the Cdk5 kinase. In vitro study confirmed the involvement of this kinase in the 5LO-dependent tau phosphorylation, which was independent of the effect on Aβ.
  
  
  CONCLUSIONS
  Our findings highlight the novel functional role that neuronal 5LO plays in exacerbating AD-related tau pathologies. They provide critical preclinical evidence to justify testing selective 5LO inhibitors for AD treatment.
authors.affiliation: Center for Translational Medicine and Department of Pharmacology, Temple University, School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Jin
authors.initials: J
authors.lastname: Chu
authors.forename: Phillip F
authors.initials: PF
authors.lastname: Giannopoulos
authors.forename: Carolina
authors.initials: C
authors.lastname: Ceballos-Diaz
authors.forename: Todd E
authors.initials: TE
authors.lastname: Golde
authors.forename: Domenico
authors.initials: D
authors.lastname: Praticò
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism; D000072197:ADAM10 Protein; D000544:Alzheimer Disease / Q000150:complications / Q000235:genetics / Q000473:pathology; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism*; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D002478:Cells, Cultured; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology*; D006801:Humans; D018782:Maze Learning; D008565:Membrane Proteins / Q000378:metabolism; D008569:Memory Disorders / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D051839:NFI Transcription Factors / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism; D010766:Phosphorylation / Q000235:genetics; D053764:Presenilin-1 / Q000235:genetics; D011863:Radioimmunoassay; D011897:Random Allocation; D015398:Signal Transduction / Q000235:genetics; D014162:Transfection; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; C077305:CTF-1 transcription factor; D008565:Membrane Proteins; D051839:NFI Transcription Factors; D010446:Peptide Fragments; D053764:Presenilin-1; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D016875:tau Proteins; D001094:Arachidonate 5-Lipoxygenase; D051360:Cyclin-Dependent Kinase 5; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491234:Adam10 protein, mouse