Author:

Keywords:

Alzheimer Disease, Amyloid beta-Protein, Amyloidosis, Animals, Anti-Inflammatory Agents, Non-Steroidal, Aspartic Endopeptidases, Cyclooxygenase 2, Disease Models, Animal, Endopeptidases, Glial Fibrillary Acidic Protein, Hippocampus, Ibuprofen, Immunoenzyme Techniques, Mice, Mice, Transgenic, Microglia, Nitric Oxide Synthase, Nitric Oxide Synthase Type II, PPAR gamma, Peptide Fragments, Prostaglandin-Endoperoxide Synthases, RNA, Messenger, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S., Thiazolidinediones, Science & Technology, Life Sciences & Biomedicine, Clinical Neurology, Neurosciences, Neurosciences & Neurology, Alzheimer's disease, PPAR, inflammation, NSAID, neurodegeneration, PROLIFERATOR-ACTIVATED-RECEPTOR, AMYLOID-PRECURSOR-PROTEIN, NONSTEROIDAL ANTIINFLAMMATORY DRUGS, EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS, NITRIC-OXIDE SYNTHASE, ALZHEIMERS-DISEASE, MOUSE MODEL, CEREBROSPINAL-FLUID, ANIMAL-MODEL, CELL-DEATH, Amyloid Precursor Protein Secretases, Amyloid beta-Peptides, Aspartic Acid Endopeptidases, Pioglitazone, 11 Medical and Health Sciences, 17 Psychology and Cognitive Sciences, Neurology & Neurosurgery, 32 Biomedical and clinical sciences, 42 Health sciences, 52 Psychology

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.