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SIRT1 Protects against Microglia-dependent Amyloid-β Toxicity through Inhibiting NF-κB Signaling
Open accessAbstract
Accumulating evidence suggests that neurodegeneration induced by pathogenic proteins depends on contributions from surrounding glia. Here we demonstrate that NF-kappaB signaling in microglia is critically involved in neuronal death induced by amyloid-beta (Abeta) peptides, which are widely presumed to cause Alzheimer disease. Constitutive inhibition of NF-kappaB signaling in microglia by expression of the nondegradable IkappaBalpha superrepressor blocked neurotoxicity, indicating a pivotal role for microglial NF-kappaB signaling in mediating Abeta toxicity. Stimulation of microglia with Abeta increased acetylation of RelA/p65 at lysine 310, which regulates the NF-kappaB pathway. Overexpression of SIRT1 deacetylase and the addition of the SIRT1 agonist resveratrol markedly reduced NF-kappaB signaling stimulated by Abeta and had strong neuroprotective effects. Our results support a glial loop hypothesis by demonstrating a critical role for microglial NF-kappaB signaling in Abeta-dependent neurodegeneration. They also implicate SIRT1 in this pathway and highlight the therapeutic potential of resveratrol and other sirtuin-activating compounds in Alzheimer disease.
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“In a recent study it was found that over expression of SIRT1 deacetylase and SIRT1 activation by resveratrol significantly protects against microglia-dependent amyloid-β toxicity by inhibiting NF-kB signaling199.”
From Mitochondrial Approaches for Neuroprotection (2008) · cites this paper as [199]
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Metadata
- Authors
- Chen, J., Zhou, Y., Mueller-Steiner, S., Chen, L.-F., Kwon, H., Yi, S., Mucke, L., & Gan, L.
- Affiliations
- Gladstone Institutes (US)
- Corresponding author
- Gan, Li
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2005-12
- Volume
- 280
- Issue
- 48
- Pages
- 40364-40374
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2074916731
- Cited by
- 740
- References
- 54
- Citations by year
- 2026: 13 · 2025: 13 · 2024: 35 · 2023: 36 · 2022: 22 · 2021: 39 · 2020: 49 · 2019: 30 · 2018: 46 · 2017: 40 · 2016: 26 · 2015: 35 · 2014: 35 · 2013: 48 · 2012: 43
- FWCI
- 17.20
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- University of California, San Francisco
- National Institute of Neurological Disorders and Stroke (NS43945, R01NS043945)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Keywords
- SIRT1, microglia, amyloid-beta, NF-κB signaling, Alzheimer's disease, neurodegeneration, resveratrol, neuroprotection
- MeSH terms
- Resveratrol, Alzheimer Disease, Animals, Bromodeoxyuridine, Cells, Cultured, Genetic Vectors, Humans, Immunohistochemistry, Lysine, Microscopy, Fluorescence, Models, Biological, Models, Genetic, Neurons, Stilbenes, Signal Transduction, Lentivirus, Amyloid beta-Peptides, NF-kappa B, Rats, Sprague-Dawley, Microglia, Genes, Reporter, Reverse Transcriptase Polymerase Chain Reaction, Sirtuins, Green Fluorescent Proteins, Rats, Sirtuin 1
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