15817521

pubmed:Citation

Pt 6

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.

eng

AIM

MEDLINE

1460-2156

Electronic

NLM

1442-53

pubmed-meshheading:15817521-Alzheimer Disease, pubmed-meshheading:15817521-Amyloid Precursor Protein Secretases, pubmed-meshheading:15817521-Amyloid beta-Peptides, pubmed-meshheading:15817521-Amyloidosis, pubmed-meshheading:15817521-Animals, pubmed-meshheading:15817521-Anti-Inflammatory Agents, Non-Steroidal, pubmed-meshheading:15817521-Aspartic Acid Endopeptidases, pubmed-meshheading:15817521-Cyclooxygenase 2, pubmed-meshheading:15817521-Disease Models, Animal, pubmed-meshheading:15817521-Endopeptidases, pubmed-meshheading:15817521-Glial Fibrillary Acidic Protein, pubmed-meshheading:15817521-Hippocampus, pubmed-meshheading:15817521-Ibuprofen, pubmed-meshheading:15817521-Immunoenzyme Techniques, pubmed-meshheading:15817521-Mice, pubmed-meshheading:15817521-Mice, Transgenic, pubmed-meshheading:15817521-Microglia, pubmed-meshheading:15817521-Nitric Oxide Synthase, pubmed-meshheading:15817521-Nitric Oxide Synthase Type II, pubmed-meshheading:15817521-PPAR gamma, pubmed-meshheading:15817521-Peptide Fragments, pubmed-meshheading:15817521-Prostaglandin-Endoperoxide Synthases, pubmed-meshheading:15817521-RNA, Messenger, pubmed-meshheading:15817521-Thiazolidinediones

Acute treatment with the PPARgamma agonist pioglitazone and ibuprofen reduces glial inflammation and Abeta1-42 levels in APPV717I transgenic mice.

Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural