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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, Freddy
Landreth, Gary E #
Issue Date: Jun-2005
Publisher: Macmillan
Series Title: Brain vol:128 issue:Pt 6 pages:1442-1453
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.
URI: 
ISSN: 0006-8950
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Department of Human Genetics - miscellaneous
Associated Laboratories - miscellaneous (-)
× corresponding author
# (joint) last author

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