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Nonsteroidal anti-inflammatory drugs repress beta-secretase gene promoter activity by the activation of PPARgamma.

ABSTRACT: Epidemiological evidence suggests that nonsteroidal anti-inflammatory drugs (NSAIDs) decrease the risk for Alzheimer's disease (AD). Certain NSAIDs can activate the peroxisome proliferator-activated receptor-gamma (PPARgamma), which is a nuclear transcriptional regulator. Here we show that PPARgamma depletion potentiates beta-secretase [beta-site amyloid precursor protein cleaving enzyme (BACE1)] mRNA levels by increasing BACE1 gene promoter activity. Conversely, overexpression of PPARgamma, as well as NSAIDs and PPARgamma activators, reduced BACE1 gene promoter activity. These results suggested that PPARgamma could be a repressor of BACE1. We then identified a PPARgamma responsive element (PPRE) in the BACE1 gene promoter. Mutagenesis of the PPRE abolished the binding of PPARgamma to the PPRE and increased BACE1 gene promoter activity. Furthermore, proinflammatory cytokines decreased PPARgamma gene transcription, and this effect was supressed by NSAIDs. We also demonstrate that in vivo treatment with PPARgamma agonists increased PPARgamma and reduced BACE1 mRNA and intracellular beta-amyloid levels. Interestingly, brain extracts from AD patients showed decreased PPARgamma expression and binding to PPRE in the BACE1 gene promoter. Our data strongly support a major role of PPARgamma in the modulation of amyloid-beta generation by inflammation and suggest that the protective mechanism of NSAIDs in AD involves activation of PPARgamma and decreased BACE1 gene transcription.

SUBMITTER: Sastre M

PROVIDER: S-EPMC1326151 | biostudies-literature | 2006 Jan

REPOSITORIES: biostudies-literature

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Nonsteroidal anti-inflammatory drugs repress beta-secretase gene promoter activity by the activation of PPARgamma.

Sastre Magdalena M Dewachter Ilse I Rossner Steffen S Bogdanovic Nenad N Rosen Evan E Borghgraef Peter P Evert Bernd O BO Dumitrescu-Ozimek Lucia L Thal Dietmar R DR Landreth Gary G Walter Jochen J Klockgether Thomas T van Leuven Fred F Heneka Michael T MT

Proceedings of the National Academy of Sciences of the United States of America 20060103 2

Epidemiological evidence suggests that nonsteroidal anti-inflammatory drugs (NSAIDs) decrease the risk for Alzheimer's disease (AD). Certain NSAIDs can activate the peroxisome proliferator-activated receptor-gamma (PPARgamma), which is a nuclear transcriptional regulator. Here we show that PPARgamma depletion potentiates beta-secretase [beta-site amyloid precursor protein cleaving enzyme (BACE1)] mRNA levels by increasing BACE1 gene promoter activity. Conversely, overexpression of PPARgamma, as ...[more]

PMID: 16407166

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Project description:Background & aimsNonsteroidal anti-inflammatory drugs (NSAIDs) have been suggested to protect against esophageal adenocarcinoma (EAC). This study examined the effect of NSAIDs on the risk of developing Barrett's esophagus (BE), the precursor lesion to EAC.MethodsWe conducted a case-control study among eligible patients scheduled for either elective esophagogastroduodenoscopy (EGD) or recruited from primary care clinics to undergo a study EGD. We compared 323 patients with BE (296 nondysplastic and 27 dysplastic) with 2 separate control groups: 1347 patients from the elective EGD group (endoscopy controls) and 502 patients from the primary care group (primary care controls) with no endoscopic or histopathologic BE. Use of aspirin products and 23 nonaspirin NSAIDs was ascertained from detailed, self-reported questionnaires. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) using multivariable logistic regression models.ResultsThere were no significant differences in self-reported NSAID use between all BE cases and all controls (58.2% vs 54.6%; P = .33); this was seen for aspirin products (43.0% vs 37.4%; P = .08) and nonaspirin NSAIDs (7.7% vs 8.9%; P = .46). These findings persisted in the multivariable model for any NSAIDs (adjusted OR, 0.89; 95% CI, 0.75-1.28), aspirin (adjusted OR, 1.16; 95% CI, 0.90-1.51), and nonaspirin NSAIDs (adjusted OR, 0.88; 95% CI, 0.55-1.39). Use of a combination of aspirin and nonaspirin NSAIDs was reported in 7.4% of cases and 8.3% of controls, and a nonsignificant inverse association with BE was seen (adjusted OR, 0.70; 95% CI, 0.44-1.11). There was no significant association between BE and daily NSAID use (adjusted OR, 1.03; 95% CI, 0.78-1.37). Similar findings were observed for comparisons involving nondysplastic or dysplastic BE cases, and endoscopy or primary care control groups separately or combined.ConclusionsThe use of NSAIDs was not associated with a reduced risk of BE. It is likely that the protective mechanism of NSAIDs on EAC occurs subsequent to the development of BE.

Dataset Information

Nonsteroidal anti-inflammatory drugs repress beta-secretase gene promoter activity by the activation of PPARgamma.

Publications

Nonsteroidal anti-inflammatory drugs repress beta-secretase gene promoter activity by the activation of PPARgamma.

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