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Series GSE234420 Query DataSets for GSE234420
Status Public on Aug 20, 2023
Title cGAS/STING drives ageing-related inflammation and neurodegeneration III
Organism Mus musculus
Experiment type Expression profiling by high throughput sequencing
Summary Low-grade inflammation is a hallmark of old age and a central driver of ageing-associated impairment and disease. Multiple factors can contribute to ageing-associated inflammation, however the molecular pathways transducing aberrant inflammatory signalling and their impact in natural ageing remain poorly understood. Here we show that the cGAS-STING signalling pathway, mediating immune sensing of DNA, is a critical driver of chronic inflammation and functional decline during ageing. Blockade of STING suppresses the inflammatory phenotypes of senescent human cells and tissues, attenuates ageing-related inflammation in multiple peripheral organs and the brain in mice, and leads to an improvement in tissue function. Focusing on the ageing brain, we reveal that activation of STING triggers reactive microglia transcriptional states, neurodegeneration and cognitive decline. Cytosolic DNA released from perturbed mitochondria elicits cGAS activity in old microglia defining a mechanism by which cGAS-STING signalling is engaged in the ageing brain. Single-nuclei RNA-sequencing (snRNA-seq) of microglia and hippocampi of a newly developed cGAS gain-of-function mouse model demonstrates that engagement of cGAS in microglia is sufficient to direct ageing-associated transcriptional microglia states leading to bystander cell inflammation, neurotoxicity and impaired memory capacity. Our findings establish the cGAS-STING pathway as a critical driver of ageing-related inflammation in peripheral organs and the brain, and reveal blockade of cGAS-STING signalling as a potential strategy to halt (neuro)degenerative processes during old age.
Overall design 20m old aged mice were treated for 16w with DMSO or H151 over 24w. Aged mice were injected intraperitoneally with 750 nmol H151 per mouse five days a week for 8 weeks. The mice were rested for 8 weeks, and 8 weeks of treatment were repeated one more time. Hippocampus were collected and compared to the hippocampus of 10w young mice
Contributor(s) Gulen MF, Samson N, Keller A, Schwabenland M, Liu C, Glück S, Thacker VV, Favre L, Mangeat B, Kroese L, Krimpenfort P, Prinz M, Ablasser A
Citation(s) 37532932
Submission date Jun 07, 2023
Last update date Aug 20, 2023
Contact name Andrea Ablasser
Organization name EPFL
Lab Ablasser
Street address route Cantonale
City Lausanne
ZIP/Postal code 1015
Country Switzerland
Platforms (1)
GPL24247 Illumina NovaSeq 6000 (Mus musculus)
Samples (9)
GSM7467237 Aged mouse brain 1, 24w DMSO treatment
GSM7467238 Aged mouse brain 2, 24w DMSO treatment
GSM7467239 Aged mouse brain 3, 24w DMSO treatment
This SubSeries is part of SuperSeries:
GSE234422 cGAS/STING drives ageing-related inflammation and neurodegeneration
BioProject PRJNA981210

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Supplementary file Size Download File type/resource
GSE234420_counts_allsamples.txt.gz 666.7 Kb (ftp)(http) TXT
GSE234420_normcounts_allsamples.txt.gz 1.4 Mb (ftp)(http) TXT
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