Please use this identifier to cite or link to this item:
http://hdl.handle.net/1942/30268
Title: | Acute treatment with the PPARgamma agonist pioglitazone and ibuprofen reduces glial inflammation and Abeta1-42 levels in APPV717I transgenic mice | Authors: | Heneka, Michael T Sastre, Magdalena Dumitrescu-Ozimek, Lucia Hanke, Anne DEWACHTER, Ilse Kuiperi, Cuno O'Banion, Kerry Klockgether, Thomas Van Leuven, Fred Landreth, Gary E |
Issue Date: | 2005 | Publisher: | OXFORD UNIV PRESS | Abstract: | Neuritic plaques in the brain of Alzheimer's disease patients are characterized by beta-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-gamma (PPARgamma) 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 PPARgamma activation. We report that an acute 7 day oral treatment of 10-month-old APPV717I mice with the PPARgamma 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 beta-secretase-1 (BACE1) mRNA and protein levels. Importantly, we observed a significant reduction of the total area and staining intensity of Abeta1-42-positive amyloid deposits in the hippocampus and cortex. Additionally, animals treated with pioglitazone revealed a 27% reduction in the levels of soluble Abeta1-42 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 | Document URI: | http://hdl.handle.net/1942/30268 | ISSN: | 0006-8950 | e-ISSN: | 1460-2156 | DOI: | 10.1093/brain/awh452 | ISI #: | 000229285700024 | Rights: | The Author (2005). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org | Category: | A1 | Type: | Research Report |
Appears in Collections: | Research publications |
Show full item record
Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.