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- Title
Alteration of cGAS-STING signaling pathway components in the mouse cortex and hippocampus during healthy brain aging.
- Authors
Passarella, Sergio; Kethiswaran, Shananthan; Brandes, Karina; I.-Chin Tsai; Cebulski, Kristin; Kröger, Andrea; Dieterich, Daniela C.; Landgraf, Peter
- Abstract
The cGAS-STING pathway is a pivotal element of the innate immune system, recognizing cytosolic DNA to initiate the production of type I interferons and pro-inflammatory cytokines. This study investigates the alterations of the cGASSTING signaling components in the cortex and hippocampus of mice aged 24 and 108 weeks. In the cortex of old mice, an increase in the dsDNA sensor protein cGAS and its product 2030-cGAMP was observed, without corresponding activation of downstream signaling, suggesting an uncoupling of cGAS activity from STING activation. This phenomenon may be attributed to increased dsDNA concentrations in the EC neurons, potentially arising from nuclear DNA damage. Contrastingly, the hippocampus did not exhibit increased cGAS activity with aging, but there was a notable elevation in STING levels, particularly in microglia, neurons and astrocytes. This increase in STING did not correlate with enhanced IRF3 activation, indicating that brain inflammation induced by the cGAS-STING pathway may manifest extremely late in the aging process. Furthermore, we highlight the role of autophagy and its interplay with the cGAS-STING pathway, with evidence of autophagy dysfunction in aged hippocampal neurons leading to STING accumulation. These findings underscore the complexity of the cGASSTING pathway's involvement in brain aging, with regional variations in activity and potential implications for neurodegenerative diseases.
- Subjects
HIPPOCAMPUS physiology; RESEARCH funding; AUTOPHAGY; T-test (Statistics); HOMEOSTASIS; BRAIN; CELLULAR aging; NEURONS; NEUROGLIA; ENZYME-linked immunosorbent assay; PROBABILITY theory; CELLULAR signal transduction; NEURODEGENERATION; REVERSE transcriptase polymerase chain reaction; DESCRIPTIVE statistics; TEMPORAL lobe; MICE; IMMUNOHISTOCHEMISTRY; MEMORY; ANIMAL experimentation; DNA damage; WESTERN immunoblotting; SPACE perception; NATURAL immunity; INFLAMMATION; MICROSCOPY; DATA analysis software; MEMBRANE proteins; CELLS; IMMUNOBLOTTING
- Publication
Frontiers in Aging Neuroscience, 2024, p1
- ISSN
1663-4365
- Publication type
Article
- DOI
10.3389/fnagi.2024.1429005