title: Modulation of nuclear factor-kappa B activity by indomethacin influences A beta levels but not A beta precursor protein metabolism in a model of Alzheimer's disease.
abstract: Epidemiological studies show that some nonsteroidal anti-inflammatory drugs, nonspecific inhibitors of the cyclooxygenase enzyme, reduce the incidence of Alzheimer's disease (AD). We determined the impact of two nonsteroidal anti-inflammatory drugs on A beta levels, deposition, and metabolism in a mouse model (the Tg2576) of AD-like amyloidosis. To this end, mice were treated with indomethacin and nimesulide continuously from 8 months of age until they were 15 months old. At the end of the study, indomethacin significantly reduced A beta(1-40) and A beta(1-42) levels in both cortex and hippocampus. This decrease was coincidental with a significant reduction of the nuclear factor (NF)-kappa B activity. By contrast, nimesulide had no effect on both A beta peptides and NF-kappa B. Consistently, mice receiving indomethacin, but no nimesulide, showed a significant reduction in the amyloid burden compared with placebo. Neither drug had an effect on plasma levels of A beta peptides or the A beta precursor protein metabolism. In vitro studies confirmed that genetic absence of this factor reduces the anti-amyloidogenic effect of indomethacin. These findings indicate that chronic administration of indomethacin by blocking the activation of the NF-kappa B significantly reduces the amyloid pathology in Tg2576 mice, and provide insights into the mechanisms by which this drug could slow progression of AD.
authors.affiliation: Department of Pharmacology, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Syaun
authors.initials: S
authors.lastname: Sung
authors.forename: Hengxuan
authors.initials: H
authors.lastname: Yang
authors.forename: Kunihiro
authors.initials: K
authors.lastname: Uryu
authors.forename: Edward B
authors.initials: EB
authors.lastname: Lee
authors.forename: Lei
authors.initials: L
authors.lastname: Zhao
authors.forename: Diana
authors.initials: D
authors.lastname: Shineman
authors.forename: John Q
authors.initials: JQ
authors.lastname: Trojanowski
authors.forename: Virginia M-Y
authors.initials: VM
authors.lastname: Lee
authors.forename: Domenico
authors.initials: D
authors.lastname: Praticò
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D002525:Cerebellar Cortex / Q000378:metabolism; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism; D007213:Indomethacin / Q000627:therapeutic use*; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008822:Mice, Transgenic; D023421:Models, Animal; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D041681:NIH 3T3 Cells / Q000187:drug effects / Q000378:metabolism; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism*; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013449:Sulfonamides / Q000008:administration & dosage
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000894:Anti-Inflammatory Agents, Non-Steroidal; D005904:Glial Fibrillary Acidic Protein; D007527:Isoenzymes; D008565:Membrane Proteins; D016328:NF-kappa B; D010446:Peptide Fragments; D012333:RNA, Messenger; D013449:Sulfonamides; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C496512:Ptgs1 protein, mouse; C012655:nimesulide; D007213:Indomethacin