Brain Advance Access originally published online on April 7, 2005
Brain 2005 128(6):1442-1453; doi:10.1093/brain/awh452
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Acute treatment with the PPAR
agonist pioglitazone and ibuprofen reduces glial inflammation and Aß1–42 levels in APPV717I transgenic mice
1 Department of Neurology, University of Bonn, Bonn, Germany, 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 and 4 Department of Neurosciences, Alzheimer Research Laboratory, Case Western Reserve University, Cleveland, OH, USA
Correspondence to: Michael T. Heneka, Department of Neurology, University of Münster, Albert-Schweitzer-Str. 33, Münster, Germany E-mail: heneka{at}uni-muenster.de
Neuritic plaques in the brain of Alzheimer's disease patients are characterized by ß-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 ß-secretase-1 (BACE1) mRNA and protein levels. Importantly, we observed a significant reduction of the total area and staining intensity of Aß1–42-positive amyloid deposits in the hippocampus and cortex. Additionally, animals treated with pioglitazone revealed a 27% reduction in the levels of soluble Aß1–42 peptide. These findings demonstrate that anti-inflammatory drugs can act rapidly to inhibit inflammatory responses in the brain and negatively modulate amyloidogenesis.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  Z. Arvanitakis, F. Grodstein, J. L. Bienias, J. A. Schneider, R. S. Wilson, J. F. Kelly, D. A. Evans, and D. A. Bennett Relation of NSAIDs to incident AD, change in cognitive function, and AD pathology Neurology, June 3, 2008; 70(23): 2219 - 2225. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. T. Kodl and E. R. Seaquist Cognitive Dysfunction and Diabetes Mellitus Endocr. Rev., June 1, 2008; 29(4): 494 - 511. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Kielian, M. Md. Syed, S. Liu, N. K. Phulwani, N. Phillips, G. Wagoner, P. D. Drew, and N. Esen The Synthetic Peroxisome Proliferator-Activated Receptor-{gamma} Agonist Ciglitazone Attenuates Neuroinflammation and Accelerates Encapsulation in Bacterial Brain Abscesses J. Immunol., April 1, 2008; 180(7): 5004 - 5016. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Hou, R. Liu, S. Ross, E. J. Smart, H. Zhu, and W. Gong Crystallographic Studies of Human MitoNEET J. Biol. Chem., November 16, 2007; 282(46): 33242 - 33246. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Hoshino, T. Nakaya, T. Homan, K.-i. Tanaka, Y. Sugimoto, W. Araki, M. Narita, S. Narumiya, T. Suzuki, and T. Mizushima Involvement of Prostaglandin E2 in Production of Amyloid-beta Peptides Both in Vitro and in Vivo J. Biol. Chem., November 9, 2007; 282(45): 32676 - 32688. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Tamaki, S. Ohtsuki, and T. Terasaki Insulin Facilitates the Hepatic Clearance of Plasma Amyloid beta-Peptide (1 40) by Intracellular Translocation of Low-Density Lipoprotein Receptor-Related Protein 1 (LRP-1) to the Plasma Membrane in Hepatocytes Mol. Pharmacol., October 1, 2007; 72(4): 850 - 855. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Ghosh, N. Patel, D. Rahn, J. McAllister, S. Sadeghi, G. Horwitz, D. Berry, K. X. Wang, and R. H. Swerdlow The Thiazolidinedione Pioglitazone Alters Mitochondrial Function in Human Neuron-Like Cells Mol. Pharmacol., June 1, 2007; 71(6): 1695 - 1702. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. L. Masters and K. Beyreuther Alzheimer's centennial legacy: prospects for rational therapeutic intervention targeting the A{beta} amyloid pathway Brain, November 1, 2006; 129(11): 2823 - 2839. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R Bordet, P Gele, P Duriez, and J-C Fruchart PPARs: a new target for neuroprotection. J. Neurol. Neurosurg. Psychiatry, March 1, 2006; 77(3): 285 - 287. [Full Text] [PDF]
|
|
|
|
 |
|
 M. Sastre, I. Dewachter, S. Rossner, N. Bogdanovic, E. Rosen, P. Borghgraef, B. O. Evert, L. Dumitrescu-Ozimek, D. R. Thal, G. Landreth, et al. Nonsteroidal anti-inflammatory drugs repress {beta}-secretase gene promoter activity by the activation of PPAR{gamma} PNAS, January 10, 2006; 103(2): 443 - 448. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. P. Townsend and D. Pratico Novel therapeutic opportunities for Alzheimer's disease: focus on nonsteroidal anti-inflammatory drugs FASEB J, October 1, 2005; 19(12): 1592 - 1601. [Abstract] [Full Text] [PDF]
|
|