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


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-1? upregulation in mice. Interestingly, the selective activation of IL-1? transcription by SIRT1 deficiency is likely mediated through hypomethylating the specific CpG sites on IL-1? proximal promoter. In humans, hypomethylation of IL-1? is strongly associated with chronological age and with elevated IL-1? transcription. Our findings reveal a novel epigenetic mechanism in aging microglia that contributes to cognitive deficits in aging and neurodegenerative diseases.

SUBMITTER: Cho SH 

PROVIDER: S-EPMC4293425 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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

Cho Seo-Hyun SH   Chen Jason A JA   Sayed Faten F   Ward Michael E ME   Ward Michael E ME   Gao Fuying F   Nguyen Thi A TA   Krabbe Grietje G   Sohn Peter Dongmin PD   Lo Iris I   Minami Sakura S   Devidze Nino N   Zhou Yungui Y   Coppola Giovanni G   Gan Li L  

The Journal of neuroscience : the official journal of the Society for Neuroscience 20150101 2


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 ro  ...[more]

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