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MK886 reduces cerebral amyloid angiopathy severity in TgCRND8 mice
Cheryl A Hawkes1, James E Shaw, Mary Brown
1Clinical and Experimental Sciences, University of Southampton, Southampton General Hospital, Southampton, UK.
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.
Insights
MK886, a 5-lipoxygenase (5-LOX) inhibitor, reduced amyloid-beta deposition and cerebral amyloid angiopathy (CAA) in Alzheimer's disease mouse models. This suggests 5-LOX inhibitors may treat CAA and AD.
Area of Science:
- Neuroscience
- Pharmacology
Background:
- Cerebral amyloid angiopathy (CAA), amyloid-beta (Aβ) deposition in brain blood vessels, is common in Alzheimer's disease (AD).
- The 5-lipoxygenase (5-LOX) pathway influences Aβ deposition, with its products activating peroxisome proliferator-activated receptors (PPARs) that clear Aβ.
Purpose of the Study:
- To investigate the effect of MK886, a 5-LOX-activating protein (FLAP) inhibitor and PPARα antagonist, on CAA severity in a mouse model of AD.
Main Methods:
- TgCRND8 mice, overexpressing amyloid precursor protein mutations, were treated with MK886.
- Brain levels of key proteins and CAA severity were assessed.
Main Results:
- MK886 treatment significantly decreased brain nicastrin and PPARα levels.
- CAA severity and parenchymal plaque load were significantly reduced in the cortex and hippocampus of MK886-treated mice.
Conclusions:
- Inhibition of 5-LOX and FLAP pathways shows potential therapeutic benefits for CAA and AD.
- MK886 demonstrated efficacy in reducing amyloid pathology in a preclinical AD model.
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