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Cited by 275Neuroinflammation and Neurodegeneration MechanismsSirtuins and Resveratrol in MedicineNeurological Disease Mechanisms and Treatments

SIRT1 Deficiency in Microglia Contributes to Cognitive Decline in Aging and Neurodegeneration via Epigenetic Regulation of IL-1β

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Cho, Seo-Hyun, Chen, Jason A., Sayed, Faten, Ward, Michael E., Gao, Fuying, Nguyen, Thi A., Krabbe, Grietje, Sohn, Peter Dongmin +6 more·2015·The Journal of Neuroscience
DOI 10.1523/jneurosci.2939-14.2015PMC PMC4293425
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Abstract

Aging is the predominant risk factor for neurodegenerative diseases. One key phenotype as the brain ages is an aberrant innate immune response characterized by proinflammation. However, the molecular mechanisms underlying aging-associated proinflammation are poorly defined. Whether chronic inflammation plays a causal role in cognitive decline in aging and neurodegeneration has not been established. Here we report a mechanistic link between chronic inflammation and aging microglia and a causal role of aging microglia in neurodegenerative cognitive deficits. We showed that SIRT1 is reduced with the aging of microglia and that microglial SIRT1 deficiency has a causative role in aging- or tau-mediated memory deficits via IL-1β upregulation in mice. Interestingly, the selective activation of IL-1β transcription by SIRT1 deficiency is likely mediated through hypomethylating the specific CpG sites on IL-1β proximal promoter. In humans, hypomethylation of IL-1β is strongly associated with chronological age and with elevated IL-1β transcription. Our findings reveal a novel epigenetic mechanism in aging microglia that contributes to cognitive deficits in aging and neurodegenerative diseases.

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  • The age-dependent increase in microglial IL-1β levels is seemingly driven by the age-dependent loss of microglial SIRT1, a NAD-dependent deacetylase that can regulate the activity of DNA methyltransferase 1 (DNMT1).

    “which is seemingly driven by the age-dependent loss of microglial SIRT1, a NADdependent deacetylase that can regulate the activity of DNA methyltransferase 1 (DNMT1) (Cho et al., 2015).”

    From TET2 Regulates the Neuroinflammatory Response in Microglia (2019) · cites this paper as Cho et al., 2015

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Authors
Cho, S.-H., Chen, J. A., Sayed, F., Ward, M. E., Gao, F., Nguyen, T. A., Krabbe, G., Sohn, P. D., Lo, I., Minami, S., Devidze, N., Zhou, Y., Coppola, G., & Gan, L.
Affiliations
  • Gladstone Institutes (US)
  • University of California, Los Angeles (US)
ORCID
Venue
The Journal of Neuroscience
Publisher
Society for Neuroscience
Published
2015-01-14
Volume
35
Issue
2
Pages
807-818
ISSN
  • 0270-6474 (ISSN-L)
  • 1529-2401
DOI
10.1523/jneurosci.2939-14.2015
PMC
PMC4293425
OpenAlex
W2054717478
Cited by
275
References
58
Citations by year
2026: 24 · 2025: 19 · 2024: 25 · 2023: 19 · 2022: 32 · 2021: 23 · 2020: 30 · 2019: 18 · 2018: 25 · 2017: 23 · 2016: 25 · 2015: 12
FWCI
15.14
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • Gladstone Institutes (RR18928)
  • National Institutes of Health (1c06rr018928-01)
  • National Institute on Aging (R01AG030207, R01AG036884, P01AG019724)
  • National Institute of Neurological Disorders and Stroke (P30NS065780, F31NS084556, P30NS062691, NS062691)
  • National Center for Research Resources (C06-RR-018928, RR18928)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
  • Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
Keywords
SIRT1, microglia, cognitive decline, aging, neurodegeneration, IL-1β, epigenetic regulation, DNA methylation, CpG sites, tau protein, memory impairment, chronic inflammation, innate immune response
MeSH terms
Aging, Animals, Cognition, Humans, Up-Regulation, Case-Control Studies, Microglia, DNA Methylation, Tauopathies, Epigenesis, Genetic, Mice, Interleukin-1beta, Sirtuin 1

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