SIRT1 Deficiency in Microglia Contributes to Cognitive Decline in Aging and Neurodegeneration via Epigenetic Regulation of IL-1β
- Seo-Hyun Cho1,3,
- Jason A. Chen5,
- Faten Sayed1,3,4,
- Michael E. Ward1,3,
- Fuying Gao5,
- Thi A. Nguyen2,
- Grietje Krabbe1,3,
- Peter Dongmin Sohn1,3,4,
- Iris Lo1,
- Sakura Minami1,3,
- Nino Devidze1,
- Yungui Zhou1,
- Giovanni Coppola5, and
- Li Gan1,3,4
- 1Gladstone Institutes of Neurological Disease,
- 2Gladstone Institutes of Cardiovascular Disease,
- 3Department of Neurology,
- 4Neuroscience Graduate Program, University of California, San Francisco, California 94158, and
- 5Departments of Psychiatry, and Biobehavioral Sciences and Neurology, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, California 90095
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Author contributions: S.-H.C. and L.G. designed research; S.-H.C., J.A.C., F.S., F.G., T.A.N., G.K., I.L., S.M., N.D., Y.Z., and G.C. performed research; M.E.W., G.K., P.D.S., S.M., and G.C. contributed unpublished reagents/analytic tools; S.-H.C., J.A.C., F.S., F.G., T.A.N., N.D., and L.G. analyzed data; S.-H.C. and L.G. wrote the paper.
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.
- Received July 17, 2014.
- Revision received November 17, 2014.
- Accepted November 19, 2014.
- Copyright © 2015 the authors 0270-6474/15/350807-12$15.00/0
