[en] 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.
Disciplines :
Neurology
Author, co-author :
HENEKA, Michael ; Department of Neurology, University of Bonn, Bonn, Germany. heneka@uni-muenster.de
Sastre, Magdalena; Department of Neurology, University of Bonn, Bonn, Germany
Dumitrescu-Ozimek, Lucia; Department of Neurology, University of Bonn, Bonn, Germany
Hanke, Anne; Department of Neurology, University of Bonn, Bonn, Germany
Dewachter, Ilse; Experimental Genetics Group, Department of Human Genetics, K. U. Leuven, Leuven, Belgium
Kuiperi, Cuno; Experimental Genetics Group, Department of Human Genetics, K. U. Leuven, Leuven, Belgium
O'Banion, Kerry; Department of Neurobiology and Anatomy, University of Rochester Medical Center, Rochester, NY, United States
Klockgether, Thomas; Department of Neurology, University of Bonn, Bonn, Germany
Van Leuven, Fred; Experimental Genetics Group, Department of Human Genetics, K. U. Leuven, Leuven, Belgium
Landreth, Gary E; Department of Neurosciences, Alzheimer Research Laboratory, Case Western Reserve University, Cleveland, OH, United States
External co-authors :
yes
Language :
English
Title :
Acute treatment with the PPARgamma agonist pioglitazone and ibuprofen reduces glial inflammation and Abeta1-42 levels in APPV717I transgenic mice.
This study was supported by a grant from the Deutsche Forschungsgemeinschaft (SFB 4000, A8) to M.T.H. and T.K., and the NIH (AG 16740, AG008012), the Blanchett Hooker Rockefeller Foundation and the CART Fund of Rotary International to G.L.
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