QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

The Journal of Neuroscience, October 29, 2003, 23(30):9796-9804

This Article Full Text Full Text (PDF) Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (83) Citing Articles via Google Scholar Google Scholar Articles by Sastre, M. Articles by Heneka, M. T. Search for Related Content PubMed PubMed Citation Articles by Sastre, M. Articles by Heneka, M. T.

 Previous Article  |  Next Article 

Cellular/Molecular
Nonsteroidal Anti-Inflammatory Drugs and Peroxisome Proliferator-Activated Receptor- Agonists Modulate Immunostimulated Processing of Amyloid Precursor Protein through Regulation of -Secretase

Magdalena Sastre,¹ Ilse Dewachter,² Gary E. Landreth,³ Timothy M. Willson,⁴ Thomas Klockgether,¹ Fred van Leuven,² and Michael T. Heneka¹

¹Department of Neurology, University of Bonn, 53127 Bonn, Germany, ²Department of Human Genetics, Experimental Genetics Group, B-3000 Leuven, Belgium, ³Alzheimer Laboratory, Case Western Reserve University, Cleveland, Ohio 44106-4928, and ⁴GlaxoSmithKline, Discovery Research, Research Triangle Park, North Carolina 27709

Long-term treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) reduces the risk for Alzheimer's disease (AD). To determine the mechanisms by which inflammation affects AD and how NSAIDs protect against it, we stimulated neuroblastoma cells stably transfected with amyloid precursor protein (APP) with proinflammatory cytokines, which increased the secretion of amyloid- and APP ectodomain. Addition of ibuprofen, indomethacin, peroxisome proliferator-activated receptor- (PPAR) agonists, or cotransfection with PPAR cDNA reversed this effect. The inhibitory action of ibuprofen and indomethacin was suppressed by PPAR antagonists. Finally, we observed that the mRNA levels, expression, and enzymatic activity of -secretase were increased by immunostimulation and normalized by NSAIDs. In conclusion, proinflammatory cytokines activate -secretase, and NSAIDs inhibit this effect through PPAR.

Key words: cytokine; amyloid precursor protein (APP); amyloid-; NSAIDs; ibuprofen; PPAR-; BACE1

---

Received May 21, 2003; revised August 26, 2003; accepted August 28, 2003.

This article has been cited by other articles:

				A. V. Woodard-Grice, A. C. McBrayer, J. K. Wakefield, Y. Zhuo, and S. L. Bellis Proteolytic Shedding of ST6Gal-I by BACE1 Regulates the Glycosylation and Function of {alpha}4{beta}1 Integrins J. Biol. Chem., September 26, 2008; 283(39): 26364 - 26373. [Abstract] [Full Text] [PDF]

				K. Wang and Y.-J. Y. Wan Nuclear Receptors and Inflammatory Diseases Experimental Biology and Medicine, May 1, 2008; 233(5): 496 - 506. [Abstract] [Full Text] [PDF]

				M. T. Heneka, M. Ramanathan, A. H. Jacobs, L. Dumitrescu-Ozimek, A. Bilkei-Gorzo, T. Debeir, M. Sastre, N. Galldiks, A. Zimmer, M. Hoehn, et al. Locus Ceruleus Degeneration Promotes Alzheimer Pathogenesis in Amyloid Precursor Protein 23 Transgenic Mice J. Neurosci., February 1, 2006; 26(5): 1343 - 1354. [Abstract] [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]

				M. T. Heneka, M. Sastre, L. Dumitrescu-Ozimek, A. Hanke, I. Dewachter, C. Kuiperi, K. O'Banion, T. Klockgether, F. Van Leuven, and G. E. Landreth Acute treatment with the PPAR{gamma} agonist pioglitazone and ibuprofen reduces glial inflammation and A{beta}1-42 levels in APPV717I transgenic mice Brain, June 1, 2005; 128(6): 1442 - 1453. [Abstract] [Full Text] [PDF]

				G. P. Lim, F. Calon, T. Morihara, F. Yang, B. Teter, O. Ubeda, N. Salem Jr, S. A. Frautschy, and G. M. Cole A Diet Enriched with the Omega-3 Fatty Acid Docosahexaenoic Acid Reduces Amyloid Burden in an Aged Alzheimer Mouse Model J. Neurosci., March 23, 2005; 25(12): 3032 - 3040. [Abstract] [Full Text] [PDF]

				A. Cordle and G. Landreth 3-Hydroxy-3-Methylglutaryl-Coenzyme A Reductase Inhibitors Attenuate {beta}-Amyloid-Induced Microglial Inflammatory Responses J. Neurosci., January 12, 2005; 25(2): 299 - 307. [Abstract] [Full Text] [PDF]

				T. A. Lanz, G. J. Fici, and K. M. Merchant Lack of Specific Amyloid-{beta}(1-42) Suppression by Nonsteroidal Anti-Inflammatory Drugs in Young, Plaque-Free Tg2576 Mice and in Guinea Pig Neuronal Cultures J. Pharmacol. Exp. Ther., January 1, 2005; 312(1): 399 - 406. [Abstract] [Full Text] [PDF]

				I. E. Camacho, L. Serneels, K. Spittaels, P. Merchiers, D. Dominguez, and B. De Strooper Peroxisome Proliferator-Activated Receptor {gamma} Induces a Clearance Mechanism for the Amyloid-{beta} Peptide J. Neurosci., December 1, 2004; 24(48): 10908 - 10917. [Abstract] [Full Text] [PDF]

				D. Zhou, C. Noviello, C. D'Ambrosio, A. Scaloni, and L. D'Adamio Growth Factor Receptor-bound Protein 2 Interaction with the Tyrosine-phosphorylated Tail of Amyloid {beta} Precursor Protein Is Mediated by Its Src Homology 2 Domain J. Biol. Chem., June 11, 2004; 279(24): 25374 - 25380. [Abstract] [Full Text] [PDF]

				A. Mouihate, L. Boisse, and Q. J. Pittman A Novel Antipyretic Action of 15-Deoxy-{Delta}12,14-Prostaglandin J2 in the Rat Brain J. Neurosci., February 11, 2004; 24(6): 1312 - 1318. [Abstract] [Full Text] [PDF]

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help