Journal Article

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

Michael T. Heneka, Magdalena Sastre, Lucia Dumitrescu-Ozimek, Anne Hanke, Ilse Dewachter, Cuno Kuiperi, Kerry O'Banion, Thomas Klockgether, Fred Van Leuven and Gary E. Landreth

in Brain

Published on behalf of The Guarantors of Brain

Volume 128, issue 6, pages 1442-1453
Published in print June 2005 | ISSN: 0006-8950
Published online April 2005 | e-ISSN: 1460-2156 | DOI: http://dx.doi.org/10.1093/brain/awh452
Acute treatment with the PPARγ agonist pioglitazone and ibuprofen reduces glial inflammation and Aβ1–42 levels in APPV717I transgenic mice

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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.

Keywords: Alzheimer's disease; PPAR; inflammation; NSAID; neurodegeneration; 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

Journal Article.  7749 words.  Illustrated.

Subjects: Neurology ; Neuroscience

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