Ibuprofen Decreases Cytokine-Induced Amyloid Beta Production in Neuronal Cells

Blasko, Imrich; Apochal, Alexandra; Boeck, Guenther; Hartmann, Tobias; Grubeck‐Loebenstein, Beatrix; Ransmayr, Gerhard

doi:10.1006/nbdi.2001.0451

Cited by 88 publications

(72 citation statements)

References 25 publications

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“…The underlying molecular mechanism was related to decreased secretion of A␤ peptides in cultured cells and in amyloid mouse models (14,22,24,(27)(28)(29). Some NSAIDs, but not all, have been shown to be able to activate PPAR␥ (15).…”

Section: Discussionmentioning

confidence: 99%

“…We sought to determine the specificity of the effect of inflammatory cytokines and ibuprofen (14,22) in MEFs either wild type or deficient in PPAR␥ (PPAR␥Ϫ͞Ϫ MEF). The latter cells lack PPAR␥ protein and mRNA as assessed by Western blotting and semiquantitative RT-PCR, respectively (Fig.…”

Section: Effect Of Ppar␥ Supression On A␤ Secretion and Bace1 Expressmentioning

confidence: 99%

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Nonsteroidal anti-inflammatory drugs repress β-secretase gene promoter activity by the activation of PPARγ

Sastre

Dewachter

Rößner

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

348

247

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

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Section: Discussionmentioning

confidence: 99%

Section: Effect Of Ppar␥ Supression On A␤ Secretion and Bace1 Expressmentioning

confidence: 99%

Nonsteroidal anti-inflammatory drugs repress β-secretase gene promoter activity by the activation of PPARγ

Sastre

Dewachter

Rößner

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

348

247

View full text Add to dashboard Cite

show abstract

“…Inflammation acts to augment disease progression via its ability to stimulate neuronal A␤ production (Blasko et al, 2001;Sastre et al, 2003;Sheng et al, 2003) and facilitate amyloid deposition (Qiao et al, 2001;Guo et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

3-Hydroxy-3-Methylglutaryl-Coenzyme A Reductase Inhibitors Attenuate β-Amyloid-Induced Microglial Inflammatory Responses

Cordle¹,

Landreth²

2005

J. Neurosci.

161

109

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Alzheimer's disease (AD) is characterized by extracellular deposits of fibrillar ␤-amyloid (A␤) in the brain, a fulminant microglialmediated inflammatory reaction, and neuronal death. The use of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) is associated with a reduced risk of AD, which has been attributed to the cholesterol-lowering actions of these drugs. Statins have been reported recently to have anti-inflammatory actions in addition to their classic lipid-lowering effects. We report that statins robustly inhibited the A␤-stimulated expression of interleukin-1␤ and inducible nitric oxide synthase and the production of nitric oxide by microglia and monocytes. Statin treatment also blocked the rac1-dependent activation of NADPH oxidase and superoxide production. The anti-inflammatory actions of the statins were attributable to their ability to reduce the levels of isoprenyl intermediates in the cholesterol biosynthetic pathway. The effect of statins could not be reversed by exogenous cholesterol supplementation, indicating that the anti-inflammatory actions are distinct from their cholesterol-lowering actions. The addition of the isoprenyl precursors, mevalonic acid, and geranylgeranyl pyrophosphate (GGpp) attenuated the statin-mediated downregulation of inflammatory markers. Prevention of protein isoprenylation by the GGpp transferase inhibitor (GGTI-286) or inhibition of Rho-family function with Clostridium difficile Toxin A blocked the inflammatory response similar to the effect of statin treatment. We argue that the statin-mediated decrease in AD risk arises from their pleiotropic actions, effecting a reduction in neuronal A␤ production and microglia-directed inflammation.

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“…Ibuprofen, flurbiprofen, indometacine and sulindac sulphide are, however, able to decrease Aβ42 production by influencing γ-secretase cleavage without affecting COX activity ( Weggen et al, 2001;Eriksen et al, 2003). Ibuprofen, as a commonly over-the-counter used NSAID, also decreases cytokine-stimulated Aβ production in human neuronal cells and astrocytes (Blasko et al, 2001). It also reduces neuritic plaque pathology and inflammation in a mouse model of AD (Lim et al, 2000).…”

Section: -Test) (B)mentioning

confidence: 99%

How chronic inflammation can affect the brain and support the development of Alzheimer's disease in old age: the role of microglia and astrocytes

et al. 2004

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SummaryA huge amount of evidence has implicated amyloid beta (Aβ β β β ) peptides and other derivatives of the amyloid precursor protein (β β β β APP) as central to the pathogenesis of Alzheimer's disease (AD). It is also widely recognized that age is the most important risk factor for AD and that the innate immune system plays a role in the development of neurodegeneration. Little is known, however, about the molecular mechanisms that underlie age-related changes of innate immunity and how they affect brain pathology. Aging is characteristically accompanied by a shift within innate immunity towards a pro-inflammatory status. Pro-inflammatory mediators such as tumour necrosis factor-α α α α or interleukin-1β β β β can then in combination with interferon-γ γ γ γ be toxic on neurons and affect the metabolism of β β β β APP such that increased concentrations of amyloidogenic peptides are produced by neuronal cells as well as by astrocytes. A disturbed balance between the production and the degradation of Aβ β β β can trigger chronic inflammatory processes in microglial cells and astrocytes and thus initiate a vicious circle. This leads to a perpetuation of the disease.

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Ibuprofen Decreases Cytokine-Induced Amyloid Beta Production in Neuronal Cells

Cited by 88 publications

References 25 publications

Nonsteroidal anti-inflammatory drugs repress β-secretase gene promoter activity by the activation of PPARγ

Nonsteroidal anti-inflammatory drugs repress β-secretase gene promoter activity by the activation of PPARγ

3-Hydroxy-3-Methylglutaryl-Coenzyme A Reductase Inhibitors Attenuate β-Amyloid-Induced Microglial Inflammatory Responses

How chronic inflammation can affect the brain and support the development of Alzheimer's disease in old age: the role of microglia and astrocytes

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