Resveratrol mitigates lipopolysaccharide‐ and Aβ‐mediated microglial inflammation by inhibiting the TLR4/NF‐κB/STAT signaling cascade
Open Access
- 25 November 2011
- journal article
- research article
- Published by Wiley in Journal of Neurochemistry
- Vol. 120 (3), 461-472
- https://doi.org/10.1111/j.1471-4159.2011.07594.x
Abstract
J. Neurochem. (2012) 120, 461–472. 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.Keywords
This publication has 79 references indexed in Scilit:
- Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's diseaseNature Genetics, 2011
- SRT1720, SRT2183, SRT1460, and Resveratrol Are Not Direct Activators of SIRT1Online Journal of Public Health Informatics, 2010
- AMP-activated Protein Kinase Signaling Activation by Resveratrol Modulates Amyloid-β Peptide MetabolismJournal of Biological Chemistry, 2010
- Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's diseaseNature Genetics, 2009
- Toll-Like Receptors in Alzheimer's DiseasePublished by Springer Science and Business Media LLC ,2009
- Dietary supplementation with resveratrol reduces plaque pathology in a transgenic model of Alzheimer's diseaseNeurochemistry International, 2009
- SIRT1 Modulation of the Acetylation Status, Cytosolic Localization, and Activity of LKB1Online Journal of Public Health Informatics, 2008
- SIRT1 Regulates Hepatocyte Lipid Metabolism through Activating AMP-activated Protein KinaseOnline Journal of Public Health Informatics, 2008
- Resveratrol stimulates AMP kinase activity in neuronsProceedings of the National Academy of Sciences of the United States of America, 2007
- Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespanNature, 2003