Nonsteroidal anti-inflammatory drugs and peroxisome proliferator-activated receptor-gamma agonists modulate immunostimulated processing of amyloid precursor protein through regulation of beta-secretase.
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-beta and APP ectodomain. Addition of ibuprofen, indomethacin, peroxisome proliferator-activated receptor-gamma (PPARgamma) agonists, or cotransfection with PPARgamma cDNA reversed this effect. The inhibitory action of ibuprofen and indomethacin was suppressed by PPARgamma antagonists. Finally, we observed that the mRNA levels, expression, and enzymatic activity of beta-secretase were increased by immunostimulation and normalized by NSAIDs. In conclusion, proinflammatory cytokines activate beta-secretase, and NSAIDs inhibit this effect through PPARgamma.
Sastre
Magdalena
M
Department of Neurology, University of Bonn, 53127 Bonn, Germany. Magdalena.Sastre@ukb.uni-bonn.de
Dewachter
Ilse
I
Landreth
Gary E
GE
Willson
Timothy M
TM
Klockgether
Thomas
T
van Leuven
Fred
F
Heneka
Michael T
MT
D053829:Amyloid Precursor Protein Secretases; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D016282:Aspartic Acid Endopeptidases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D016207:Cytokines / Q000494:pharmacology; D010450:Endopeptidases / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007052:Ibuprofen / Q000494:pharmacology; D051379:Mice; D009447:Neuroblastoma / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism*; D000077205:Pioglitazone; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology; D014157:Transcription Factors / Q000819:agonists* / Q000378:metabolism
D016564:Amyloid beta-Protein Precursor; D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D045162:Thiazolidinediones; D014157:Transcription Factors; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C509282:Bace1 protein, mouse; D007052:Ibuprofen; D000077205:Pioglitazone