title: Resveratrol mitigates lipopolysaccharide- and Aβ-mediated microglial inflammation by inhibiting the TLR4/NF-κB/STAT signaling cascade.
abstract: Activation of microglia, the resident macrophages of the brain, around the amyloid plaques is a key hallmark of Alzheimer's disease (AD). Recent evidence in mouse models indicates that microglia are required for the neurodegenerative process of AD. Amyloid-β (Aβ) peptides, the core components of the amyloid plaques, can trigger microglial activation by interacting with several Toll-like receptors (TLRs), including TLR4. In this study, we show that resveratrol, a natural polyphenol associated with anti-inflammatory effects and currently in clinical trials for AD, prevented the activation of murine RAW 264.7 macrophages and microglial BV-2 cells treated with the TLR4 ligand, lipopolysaccharide (LPS). Resveratrol preferentially inhibited nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) activation upon LPS stimulation by interfering with IKK and IκB phosphorylation, an effect that potently reduced the transcriptional stimulation of several NF-κB target genes, including tumor necrosis factor-α and interleukin-6. Consequently, downstream phosphorylation of signal transducer and activator of transcription (STAT)1 and STAT3 upon LPS stimulation was also inhibited by resveratrol. We found that resveratrol acted upstream in the activation cascade by interfering with TLR4 oligomerization upon receptor stimulation. Resveratrol treatment also prevented the pro-inflammatory effect of fibrillar Aβ on macrophages by potently inhibiting the effect of Aβ on IκB phosphorylation, activation of STAT1 and STAT3, and on tumor necrosis factor-α and interleukin-6 secretion. Importantly, orally administered resveratrol in a mouse model of cerebral amyloid deposition lowered microglial activation associated with cortical amyloid plaque formation. Together this work provides strong evidence that resveratrol has in vitro and in vivo anti-inflammatory effects against Aβ-triggered microglial activation. Further studies in cell culture systems showed that resveratrol acted via a mechanism involving the TLR4/NF-κB/STAT signaling cascade.
authors: The Litwin-Zucker Research Center for the Study of Alzheimer's Disease, The Feinstein Institute for Medical Research, Manhasset, New York, USA.
authors: Hemachander
authors: H
authors: Capiralla
authors: Valérie
authors: V
authors: Vingtdeux
authors: Haitian
authors: H
authors: Zhao
authors: Roman
authors: R
authors: Sankowski
authors: Yousef
authors: Y
authors: Al-Abed
authors: Peter
authors: P
authors: Davies
authors: Philippe
authors: P
authors: Marambaud
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000494:pharmacology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology / Q000627:therapeutic use*; D002461:Cell Line, Transformed; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004347:Drug Interactions; D006801:Humans; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism; D018836:Inflammation Mediators / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects*; D000072000:NF-KappaB Inhibitor alpha; D053764:Presenilin-1 / Q000235:genetics; D000077185:Resveratrol; D015398:Signal Transduction / Q000187:drug effects*; D018709:Statistics, Nonparametric; D013267:Stilbenes / Q000494:pharmacology / Q000627:therapeutic use*; D013997:Time Factors; D051193:Toll-Like Receptors / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; D020672:I-kappa B Proteins; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; C508853:PSEN1 protein, human; D053764:Presenilin-1; D013267:Stilbenes; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; D000077185:Resveratrol