MK886 reduces cerebral amyloid angiopathy severity in TgCRND8 mice

Hawkes, Cheryl A, Shaw, James E., Brown, Mary, Sampson, Anthony, McLaurin, JoAnne and Carare, Roxana-Octavia (2014) MK886 reduces cerebral amyloid angiopathy severity in TgCRND8 mice. Neurodegenerative Diseases, 13 (1), 17-23. (doi: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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Contributors

Author: Anthony Sampson

Author: Roxana-Octavia Carare

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