Acute treatment with the PPARγ agonist pioglitazone and ibuprofen reduces glial inflammation and Aβ1–42 levels in APPV717I transgenic mice (original) (raw)

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Correspondence to: Michael T. Heneka, Department of Neurology, University of Münster, Albert-Schweitzer-Str. 33, Münster, Germany E-mail: heneka@uni-muenster.de

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Revision received:

19 October 2004

Accepted:

21 January 2005

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Michael T. Heneka, Magdalena Sastre, Lucia Dumitrescu-Ozimek, Anne Hanke, Ilse Dewachter, Cuno Kuiperi, Kerry O'Banion, Thomas Klockgether, Fred Van Leuven, Gary E. Landreth, Acute treatment with the PPARγ agonist pioglitazone and ibuprofen reduces glial inflammation and Aβ1–42 levels in APPV717I transgenic mice, Brain, Volume 128, Issue 6, June 2005, Pages 1442–1453, https://doi.org/10.1093/brain/awh452
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Abstract

Neuritic plaques in the brain of Alzheimer's disease patients are characterized by β-amyloid deposits associated with a glia-mediated inflammatory response. Non-steroidal anti-inflammatory drug (NSAID) therapy reduces Alzheimer's disease risk and ameliorates microglial reactivity in Alzheimer's disease brains; however, the molecular mechanisms subserving this effect are not yet clear. Since several NSAIDs bind to and activate the nuclear receptor peroxisome proliferator-activated receptor-γ (PPARγ) which acts to inhibit the expression of proinflammatory genes, this receptor appears a good candidate to mediate the observed anti-inflammatory effects. Recent data in vitro suggested that NSAIDs negatively regulate microglial activation and immunostimulated amyloid precursor protein processing via PPARγ activation. We report that an acute 7 day oral treatment of 10-month-old APPV717I mice with the PPARγ agonist pioglitazone or the NSAID ibuprofen resulted in a reduction in the number of activated microglia and reactive astrocytes in the hippocampus and cortex. Drug treatment reduced the expression of the proinflammatory enzymes cyclooxygenase 2 (COX2) and inducible nitric oxide synthase (iNOS). In parallel to the suppression of inflammatory markers, pioglitazone and ibuprofen treatment decreased β-secretase-1 (BACE1) mRNA and protein levels. Importantly, we observed a significant reduction of the total area and staining intensity of Aβ1–42-positive amyloid deposits in the hippocampus and cortex. Additionally, animals treated with pioglitazone revealed a 27% reduction in the levels of soluble Aβ1–42 peptide. These findings demonstrate that anti-inflammatory drugs can act rapidly to inhibit inflammatory responses in the brain and negatively modulate amyloidogenesis.

Aβ = amyloid β, APP = amyloid precursor protein, COX = cyclooxygenase, BACE-1 = β-secretase-1, GAPDH = glyceraldehyde-3-phosphate dehydrogenase, GFAP = glial fibrillary acidic protein, IB4 = isolectin B4, iNOS = inducible nitric oxide synthase, NSAID = non-steroidal anti-inflammatory drug, PPARγ = peroxisome proliferator-activated receptor-γ, PCR = polymerase chain reaction

© The Author (2005). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please e-mail: journals.permissions@oupjournals.org

Topic:

• amyloid
• anti-inflammatory agents
• pharmacotherapy
• cyclooxygenase-2
• pioglitazone
• alzheimer's disease
• inflammation
• anti-inflammatory agents, non-steroidal
• astrocytes
• hippocampus
• ibuprofen
• mice, transgenic
• microglia
• nitric oxide synthase
• peptides
• rna, messenger
• senile plaques
• brain
• mice
• agonists
• bace1 gene

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