title: SIRT1 deficiency in microglia contributes to cognitive decline in aging and neurodegeneration via epigenetic regulation of IL-1β.
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.
authors.affiliation: Gladstone Institutes of Neurological Disease, Department of Neurology.
authors.forename: Seo-Hyun
authors.initials: SH
authors.lastname: Cho
authors.affiliation: Departments of Psychiatry, and Biobehavioral Sciences and Neurology, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, California 90095.
authors.forename: Jason A
authors.identifier: http://orcid.org/0000-0003-3158-9471
authors.initials: JA
authors.lastname: Chen
authors.affiliation: Gladstone Institutes of Neurological Disease, Department of Neurology, Neuroscience Graduate Program, University of California, San Francisco, California 94158, and.
authors.forename: Faten
authors.initials: F
authors.lastname: Sayed
authors.affiliation: Gladstone Institutes of Neurological Disease, Department of Neurology.
authors.forename: Michael E
authors.identifier: http://orcid.org/0000-0002-7446-5674
authors.initials: ME
authors.lastname: Ward
authors.affiliation: Departments of Psychiatry, and Biobehavioral Sciences and Neurology, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, California 90095.
authors.forename: Fuying
authors.initials: F
authors.lastname: Gao
authors.affiliation: Gladstone Institutes of Cardiovascular Disease.
authors.forename: Thi A
authors.initials: TA
authors.lastname: Nguyen
authors.affiliation: Gladstone Institutes of Neurological Disease, Department of Neurology.
authors.forename: Grietje
authors.initials: G
authors.lastname: Krabbe
authors.affiliation: Gladstone Institutes of Neurological Disease, Department of Neurology, Neuroscience Graduate Program, University of California, San Francisco, California 94158, and.
authors.forename: Peter Dongmin
authors.initials: PD
authors.lastname: Sohn
authors.affiliation: Gladstone Institutes of Neurological Disease.
authors.forename: Iris
authors.initials: I
authors.lastname: Lo
authors.affiliation: Gladstone Institutes of Neurological Disease, Department of Neurology.
authors.forename: Sakura
authors.initials: S
authors.lastname: Minami
authors.affiliation: Gladstone Institutes of Neurological Disease.
authors.forename: Nino
authors.initials: N
authors.lastname: Devidze
authors.affiliation: Gladstone Institutes of Neurological Disease.
authors.forename: Yungui
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Departments of Psychiatry, and Biobehavioral Sciences and Neurology, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, California 90095.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Coppola
authors.affiliation: Gladstone Institutes of Neurological Disease, Department of Neurology, Neuroscience Graduate Program, University of California, San Francisco, California 94158, and lgan@gladstone.ucsf.edu.
authors.forename: Li
authors.initials: L
authors.lastname: Gan
mesh_terms: D000375:Aging / Q000378:metabolism*; D000818:Animals; D016022:Case-Control Studies; D003071:Cognition; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D006801:Humans; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D017628:Microglia / Q000378:metabolism*; D056564:Sirtuin 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D024801:Tauopathies / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D053583:Interleukin-1beta; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1
keywords: NF-κ B; epigenetic; innate immunity; interleukin; memory deficits; neuroinflammation