MK886 reduces cerebral amyloid angiopathy severity in TgCRND8 mice

Neurodegener Dis. 2014;13(1):17-23. doi: 10.1159/000351096. Epub 2013 Sep 6.

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.

Conclusion: These data suggest that 5-LOX and FLAP inhibitors may be useful in the treatment of CAA and AD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 5-Lipoxygenase-Activating Protein Inhibitors / therapeutic use*
  • Amyloid beta-Protein Precursor / genetics
  • Animals
  • Brain / drug effects
  • Brain / metabolism
  • Brain / pathology
  • Cerebral Amyloid Angiopathy / drug therapy*
  • Cerebral Amyloid Angiopathy / metabolism
  • Cerebral Amyloid Angiopathy / pathology
  • Female
  • Humans
  • Indoles / therapeutic use*
  • Male
  • Mice
  • Mice, Transgenic
  • Plaque, Amyloid / drug therapy
  • Plaque, Amyloid / pathology

Substances

  • 5-Lipoxygenase-Activating Protein Inhibitors
  • APP protein, human
  • Amyloid beta-Protein Precursor
  • Indoles
  • MK-886