Journal
JOURNAL OF NEUROSCIENCE
Volume 35, Issue 2, Pages 807-818Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.2939-14.2015
Keywords
epigenetic; innate immunity; interleukin; memory deficits; neuroinflammation; NF-kappa B
Categories
Funding
- NIH [1R01AG036884, R01AG030207, 1F31NS084556]
- S.D. Bechtel Jr Foundation
- Consortium for Frontotemporal dementia
- NINDS Informatics Center for Neurogenetics and Neurogenomics [P30 NS062691]
- National Center for Research Resources [RR18928]
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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-1 beta upregulation in mice. Interestingly, the selective activation of IL-1 beta transcription by SIRT1 deficiency is likely mediated through hypomethylating the specific CpG sites on IL-1 beta proximal promoter. In humans, hypomethylation of IL-1 beta is strongly associated with chronological age and with elevated IL-1 beta 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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