Acute treatment with the PPARgamma agonist pioglitazone and ibuprofen reduces glial inflammation and Abeta1-42 levels in APPV717I transgenic mice.
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.
Heneka
Michael T
MT
Department of Neurology, University of Bonn, Bonn, Germany. heneka@uni-muenster.de
Sastre
Magdalena
M
Dumitrescu-Ozimek
Lucia
L
Hanke
Anne
A
Dewachter
Ilse
I
Kuiperi
Cuno
C
O'Banion
Kerry
K
Klockgether
Thomas
T
Van Leuven
Fred
F
Landreth
Gary E
GE
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000686:Amyloidosis / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism; D051546:Cyclooxygenase 2; D004195:Disease Models, Animal; D010450:Endopeptidases; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D007052:Ibuprofen / Q000627:therapeutic use*; D007124:Immunoenzyme Techniques; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D047495:PPAR gamma / Q000819:agonists; D010446:Peptide Fragments / Q000378:metabolism*; D000077205:Pioglitazone; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D045162:Thiazolidinediones / Q000627:therapeutic use*
D016229:Amyloid beta-Peptides; D000894:Anti-Inflammatory Agents, Non-Steroidal; D005904:Glial Fibrillary Acidic Protein; D047495:PPAR gamma; D010446:Peptide Fragments; D012333:RNA, Messenger; D045162:Thiazolidinediones; C075222:amyloid beta-protein (1-42); D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse; D007052:Ibuprofen; D000077205:Pioglitazone