title: MK886 reduces cerebral amyloid angiopathy severity in TgCRND8 mice.
abstract: BACKGROUND
  Deposition of amyloid-β (Aβ) in blood vessel walls as cerebral amyloid angiopathy (CAA) is observed in the majority of Alzheimer's disease (AD) brains. Inhibition of the 5-lipoxygenase (5-LOX) pathway has recently been suggested to play a role in reducing parenchymal Aβ deposition. However, products of the 5-LOX pathway also activate the peroxisome proliferator-activated receptor (PPAR) family, which promotes clearance of Aβ from the brain.
  
  
  METHODS
  In the present study, we investigated the effect of MK886, a 5-LOX-activating protein (FLAP) inhibitor and PPARα antagonist, on CAA severity in TgCRND8 mice overexpressing the human Swedish and Indiana amyloid precursor protein mutations.
  
  
  RESULTS
  We found that MK886 significantly reduced brain levels of nicastrin and PPARα, but did not affect levels of β-secretase, apolipoprotein E or low-density lipoprotein receptor-related protein-1. CAA severity and parenchymal plaque load was significantly decreased in both the cortex and hippocampus of mice treated with MK886 compared to control mice.
  
  
  CONCLUSIONS
  These data suggest that 5-LOX and FLAP inhibitors may be useful in the treatment of CAA and AD.
authors.affiliation: Clinical and Experimental Sciences, University of Southampton, Southampton General Hospital, Southampton, UK.
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Hawkes
authors.forename: James E
authors.initials: JE
authors.lastname: Shaw
authors.forename: Mary
authors.initials: M
authors.lastname: Brown
authors.forename: Anthony P
authors.initials: AP
authors.lastname: Sampson
authors.forename: JoAnne
authors.initials: J
authors.lastname: McLaurin
authors.forename: Roxana O
authors.initials: RO
authors.lastname: Carare
mesh_terms: D058946:5-Lipoxygenase-Activating Protein Inhibitors / Q000627:therapeutic use*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016657:Cerebral Amyloid Angiopathy / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D007211:Indoles / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D058225:Plaque, Amyloid / Q000188:drug therapy / Q000473:pathology; D002722:Chlorobenzenes
chemical_list: D058946:5-Lipoxygenase-Activating Protein Inhibitors; D016564:Amyloid beta-Protein Precursor; D007211:Indoles; C545487:APP protein, human; C060893:MK-886; D002722:Chlorobenzenes