Brain Advance Access published online on April 7, 2005
Brain, doi:10.1093/brain/awh452
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1 Department of Neurology, University of Bonn, Bonn, Germany
* To whom correspondence should be addressed. Summary Neuritic plaques in the brain of Alzheimer's disease patients are characterized by
Received August 31, 2004
Revised October 19, 2004
Accepted January 21, 2005
Article
Acute treatment with the PPAR
agonist pioglitazone and ibuprofen reduces glial inflammation and A
1-42 levels in APPV717I transgenic mice
2 Experimental Genetics Group, Department of Human Genetics, K.U. Leuven, Leuven, Belgium
3 Department of Neurobiology and Anatomy, University of Rochester Medical Center, Rochester, NY, USA
4 Department of Neurosciences, Alzheimer Research Laboratory, Case Western Reserve University, Cleveland, OH, USA
Michael T. Heneka, E-mail: heneka{at}uni-muenster.de
Abstract 
-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-
(PPAR) 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 PPAR activation. We report that an acute 7 day oral treatment of 10-month-old APPV717I mice with the PPAR 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 -secretase-1 (BACE1) mRNA and protein levels. Importantly, we observed a significant reduction of the total area and staining intensity of A1-42-positive amyloid deposits in the hippocampus and cortex. Additionally, animals treated with pioglitazone revealed a 27% reduction in the levels of soluble A1-42 peptide. These findings demonstrate that anti-inflammatory drugs can act rapidly to inhibit inflammatory responses in the brain and negatively modulate amyloidogenesis.
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