Title | SIRT1 deficiency in microglia contributes to cognitive decline in aging and neurodegeneration via epigenetic regulation of IL-1β. |
Publication Type | Journal Article |
Year of Publication | 2015 |
Authors | Cho 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 |
Journal | J Neurosci |
Volume | 35 |
Issue | 2 |
Pagination | 807-18 |
Date Published | 2015 Jan 14 |
ISSN | 1529-2401 |
Keywords | Aging, 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. |
DOI | 10.1523/JNEUROSCI.2939-14.2015 |
Alternate Journal | J. Neurosci. |
PubMed ID | 25589773 |
PubMed Central ID | PMC4293425 |
Grant List | 1R01AG036884 / 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 |