MK886 reduces cerebral amyloid angiopathy severity in TgCRND8 mice

Hawkes, C. A.; Shaw, J. E.; Brown, M.; Sampson, A. P.; McLaurin, J. and Carare, R. O. (2013). MK886 reduces cerebral amyloid angiopathy severity in TgCRND8 mice. Neurodegenerative Diseases, 13(1) pp. 17–23.

DOI: https://doi.org/10.1159/000351096

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.

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