Cited by 743Neuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatmentsSirtuins and Resveratrol in Medicine

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SIRT1 Protects against Microglia-dependent Amyloid-β Toxicity through Inhibiting NF-κB Signaling

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Chen, Jennifer, Zhou, Yungui, Mueller-Steiner, Sarah, Chen, Lin-Feng, Kwon, Hakju, Yi, Saili, Mucke, Lennart, Gan, Li·2005·Journal of Biological Chemistry

DOI 10.1074/jbc.m509329200

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Abstract

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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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
ORCID: Chen, Jennifer
Chen, Lin-Feng
Mucke, Lennart
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)
DOI: 10.1074/jbc.m509329200
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: cc-by
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
creativecommons.org/licenses/by/4.0/ (vor, 5422 d)
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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SIRT1 Protects against Microglia-dependent Amyloid-β Toxicity through Inhibiting NF-κB Signaling

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