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SIRT1 deficiency in microglia contributes to cognitive decline in aging and neurodegeneration via epigenetic regulation of IL-1β.

TitleSIRT1 deficiency in microglia contributes to cognitive decline in aging and neurodegeneration via epigenetic regulation of IL-1β.
Publication TypeJournal Article
Year of Publication2015
AuthorsCho S-H, Chen JA, Sayed F, Ward ME, Gao F, Nguyen TA, Krabbe G, Sohn PDongmin, Lo I, Minami S, Devidze N, Zhou Y, Coppola G, Gan L
JournalJ Neurosci
Volume35
Issue2
Pagination807-18
Date Published2015 Jan 14
ISSN1529-2401
KeywordsAging, Animals, Case-Control Studies, Cognition, DNA Methylation, Epigenesis, Genetic, Humans, Interleukin-1beta, Mice, Microglia, Sirtuin 1, Tauopathies, Up-Regulation
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.

DOI10.1523/JNEUROSCI.2939-14.2015
Alternate JournalJ. Neurosci.
PubMed ID25589773
PubMed Central IDPMC4293425
Grant List1R01AG036884 / AG / NIA NIH HHS / United States
R01 AG036884 / AG / NIA NIH HHS / United States
P30 NS062691 / NS / NINDS NIH HHS / United States
RR18928 / RR / NCRR NIH HHS / United States
R01AG030207 / AG / NIA NIH HHS / United States
P30 NS065780 / NS / NINDS NIH HHS / United States
P01 AG019724 / AG / NIA NIH HHS / United States
1F31NS084556 / NS / NINDS NIH HHS / United States
R01 AG030207 / AG / NIA NIH HHS / United States
F31 NS084556 / NS / NINDS NIH HHS / United States
C06 RR018928 / RR / NCRR NIH HHS / United States