Nonsteroidal anti-inflammatory drugs and peroxisome proliferator-activated receptor-gamma agonists modulate immunostimulated processing of amyloid precursor protein through regulation of beta-secretase

Magdalena Sastre; Ilse Dewachter; Gary E Landreth; Timothy M Willson; Thomas Klockgether; Fred van Leuven; Michael T Heneka

doi:10.1523/JNEUROSCI.23-30-09796.2003

Nonsteroidal anti-inflammatory drugs and peroxisome proliferator-activated receptor-gamma agonists modulate immunostimulated processing of amyloid precursor protein through regulation of beta-secretase

J Neurosci. 2003 Oct 29;23(30):9796-804. doi: 10.1523/JNEUROSCI.23-30-09796.2003.

Authors

Magdalena Sastre¹, Ilse Dewachter, Gary E Landreth, Timothy M Willson, Thomas Klockgether, Fred van Leuven, Michael T Heneka

Affiliation

¹ Department of Neurology, University of Bonn, 53127 Bonn, Germany. Magdalena.Sastre@ukb.uni-bonn.de

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amyloid Precursor Protein Secretases
Amyloid beta-Protein Precursor / metabolism*
Animals
Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
Aspartic Acid Endopeptidases / drug effects
Aspartic Acid Endopeptidases / genetics
Aspartic Acid Endopeptidases / metabolism*
Cell Line, Tumor
Cytokines / pharmacology
Endopeptidases / drug effects
Endopeptidases / metabolism
Enzyme Inhibitors / pharmacology
Humans
Ibuprofen / pharmacology
Mice
Neuroblastoma / drug therapy
Neuroblastoma / immunology
Neuroblastoma / metabolism*
Pioglitazone
Protein Processing, Post-Translational / drug effects*
RNA, Messenger / metabolism
Receptors, Cytoplasmic and Nuclear / agonists*
Receptors, Cytoplasmic and Nuclear / metabolism
Thiazolidinediones / pharmacology
Transcription Factors / agonists*
Transcription Factors / metabolism

Substances

Amyloid beta-Protein Precursor
Anti-Inflammatory Agents, Non-Steroidal
Cytokines
Enzyme Inhibitors
RNA, Messenger
Receptors, Cytoplasmic and Nuclear
Thiazolidinediones
Transcription Factors
Amyloid Precursor Protein Secretases
Endopeptidases
Aspartic Acid Endopeptidases
BACE1 protein, human
Bace1 protein, mouse
Ibuprofen
Pioglitazone