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MK886 reduces cerebral amyloid angiopathy severity in TgCRND8 mice

MK886 reduces cerebral amyloid angiopathy severity in TgCRND8 mice
MK886 reduces cerebral amyloid angiopathy severity in TgCRND8 mice
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.
1660-2854
17-23
Hawkes, Cheryl A
031a17ac-0931-4ff9-93cc-df8cb58e14f7
Shaw, James E.
14368f86-62b9-40f1-98f7-25c2b58c3350
Brown, Mary
28735aef-658a-4120-853f-29e986c94fc4
Sampson, Anthony
4ca76f6f-ff35-425d-a7e7-c2bd2ea2df60
McLaurin, JoAnne
196bc965-5bf0-4168-8963-15afe2170798
Carare, Roxana-Octavia
0478c197-b0c1-4206-acae-54e88c8f21fa
Hawkes, Cheryl A
031a17ac-0931-4ff9-93cc-df8cb58e14f7
Shaw, James E.
14368f86-62b9-40f1-98f7-25c2b58c3350
Brown, Mary
28735aef-658a-4120-853f-29e986c94fc4
Sampson, Anthony
4ca76f6f-ff35-425d-a7e7-c2bd2ea2df60
McLaurin, JoAnne
196bc965-5bf0-4168-8963-15afe2170798
Carare, Roxana-Octavia
0478c197-b0c1-4206-acae-54e88c8f21fa

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).

Record type: Article

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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More information

e-pub ahead of print date: 6 September 2013
Published date: January 2014
Organisations: Faculty of Medicine

Identifiers

Local EPrints ID: 361474
URI: http://eprints.soton.ac.uk/id/eprint/361474
ISSN: 1660-2854
PURE UUID: 740c0775-7835-4387-9100-746788601cbc
ORCID for Roxana-Octavia Carare: ORCID iD orcid.org/0000-0001-6458-3776

Catalogue record

Date deposited: 22 Jan 2014 10:26
Last modified: 09 Nov 2021 02:58

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Contributors

Author: Cheryl A Hawkes
Author: James E. Shaw
Author: Mary Brown
Author: Anthony Sampson
Author: JoAnne McLaurin

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