Nonsteroidal Anti-Inflammatory Drugs and Peroxisome Proliferator-Activated Receptor-γ Agonists Modulate Immunostimulated Processing of Amyloid Precursor Protein through Regulation of β-Secretase
Magdalena Sastre,Ilse Dewachter,Gary E Landreth,Timothy M. Willson,Thomas Klockgether,Freddy Van Leuven,M. T. Heneka +6 more
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TLDR
Proinflammatory cytokines activate β-secretase, and NSAIDs inhibit this effect through PPARγ, and it is observed that the mRNA levels, expression, and enzymatic activity of β- secretase were increased by immunostimulation and normalized by NSAIDs.Abstract:
Long-term treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) reduces the risk for Alzheimer9s 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-β and APP ectodomain. Addition of ibuprofen, indomethacin, peroxisome proliferator-activated receptor-γ (PPARγ) agonists, or cotransfection with PPARγ cDNA reversed this effect. The inhibitory action of ibuprofen and indomethacin was suppressed by PPARγ antagonists. Finally, we observed that the mRNA levels, expression, and enzymatic activity of β-secretase were increased by immunostimulation and normalized by NSAIDs. In conclusion, proinflammatory cytokines activate β-secretase, and NSAIDs inhibit this effect through PPARγ.read more
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Neuroinflammation in Alzheimer's disease
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References
More filters
Journal ArticleDOI
Inflammation and Alzheimer's disease.
Haruhiko Akiyama,Steven W. Barger,Scott R. Barnum,B Bradt,Jürgen Bauer,Greg M. Cole,Neil R. Cooper,Piet Eikelenboom,Mark R. Emmerling,Bernd L. Fiebich,Caleb E. Finch,Sally A. Frautschy,W. S. T. Griffin,Harald Hampel,Michael Hüll,Gary E. Landreth,Lih-Fen Lue,Robert E. Mrak,Ian R. A. Mackenzie,Patrick L. McGeer,M K O'Banion,Joel S. Pachter,Giulio Maria Pasinetti,C Plata-Salaman,Joseph G. Rogers,Russell E. Rydel,Yueyang Shen,Wolfgang J. Streit,Ronald Strohmeyer,I Tooyoma,F L van Muiswinkel,R. Veerhuis,David G. Walker,Scott D. Webster,Beatrice Hauss–Wegrzyniak,Gary L. Wenk,Tony Wyss-Coray +36 more
TL;DR: By better understanding AD inflammatory and immunoregulatory processes, it should be possible to develop anti-inflammatory approaches that may not cure AD but will likely help slow the progression or delay the onset of this devastating disorder.
Journal ArticleDOI
PPAR-γ agonists inhibit production of monocyte inflammatory cytokines
TL;DR: Inhibition of cytokine production may help to explain the incremental therapeutic benefit of NSAIDs observed in the treatment of rheumatoid arthritis at plasma drug concentrations substantially higher than are required to inhibit prostaglandin G/H synthase (cyclooxygenase).
Journal ArticleDOI
The PPARs: from orphan receptors to drug discovery.
Journal ArticleDOI
Brain interleukin 1 and S-100 immunoreactivity are elevated in Down syndrome and Alzheimer disease
W. S.T. Griffin,L. C. Stanley,C. Ling,L. White,V. MacLeod,L. J. Perrot,Charles L. White,C. Araoz +7 more
TL;DR: The data suggest that increased expression of S-100 in Down syndrome, resulting from duplication of the gene on chromosome 21 that encodes the beta subunit ofS-100, may be augmented by elevation of interleukin 1, which may promote the astrogliosis in Alzheimer disease.
Journal ArticleDOI
A subset of NSAIDs lower amyloidogenic Aβ42 independently of cyclooxygenase activity
Sascha Weggen,Jason L. Eriksen,Pritam Das,Sarah A. Sagi,Rong Wang,Claus U. Pietrzik,Kirk A. Findlay,Tawnya E. Smith,Michael P. Murphy,Thomas Bulter,David E. Kang,Numa R. Marquez-Sterling,Todd E. Golde,Edward H. Koo +13 more
TL;DR: It is reported that the NSAIDs ibuprofen, indomethacin and sulindac sulphide preferentially decrease the highly amyloidogenic Aβ42 peptide (the 42-residue isoform of the amyloids-β peptide) produced from a variety of cultured cells by as much as 80%.
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