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| Status |
Public on Oct 01, 2014 |
| Title |
SIRT1 deficiency in microglia contributes to cognitive decline in aging and neurodegeneration via epigenetic regulation of IL-1beta |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by array
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| Summary |
Aging is the predominant risk factor for neurodegenerative diseases. One key phenotype as brain ages is the 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 established a mechanistic link between chronic inflammation and aging microglia, and demonstrated a causal role of aging microglia in neurodegenerative cognitive deficits. Expression of microglial SIRT1 reduces with the aging of microglia. Genetic reduction of microglial SIRT1 elevates IL-1β selectively, and exacerbates cognitive deficits in aging and in transgenic mouse models of frontotemporal dementia (FTD). Interestingly, the selective activation of IL-1β transcription by SIRT1 deficiency is likely mediated through hypomethylating the proximal promoter of IL-1β. Consistent with our findings in mice, selective hypomethylation of IL-1β at two CpG sites are found in normal aging humans and demented patients with tauopathy. Our findings reveal a novel epigenetic mechanism in aging microglia that contributes to cognitive deficits in neurodegenerative diseases.
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| Overall design |
Study of changes related to alterations of SIRT1 levels in microglia of young and aged animals and in models of neurodegenerative dementia
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| Contributor(s) |
Cho S, Chen J, Ward ME, Gao F, Krabbe G, Sohn PD, Lo I, Minami S, Devidze N, Zhou Y, Coppola G, Gan L |
| Citation(s) |
25589773 |
| Submission date |
Apr 02, 2014 |
| Last update date |
Jun 14, 2018 |
| Contact name |
Giovanni Coppola |
| E-mail(s) |
gcoppola@ucla.edu
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| Phone |
310-794-4172
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| Organization name |
UCLA
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| Department |
Psychiatry and Neurology
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| Lab |
Neurogenetics
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| Street address |
1524 Gonda, 695 Charles Young Drive South
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| City |
Los Angeles |
| State/province |
CA |
| ZIP/Postal code |
90095 |
| Country |
USA |
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| Platforms (1) |
| GPL6885 |
Illumina MouseRef-8 v2.0 expression beadchip |
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| Samples (16)
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| Relations |
| BioProject |
PRJNA243353 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE56452_RAW.tar |
3.1 Mb |
(http)(custom) |
TAR |
| GSE56452_non-normalized.txt.gz |
1.7 Mb |
(ftp)(http) |
TXT |
| Processed data included within Sample table |
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