Faculty, Staff and Student Publications
Language
English
Publication Date
6-18-2024
Journal
Molecular Neurodegeneration
DOI
10.1186/s13024-024-00736-6
PMID
38886816
PMCID
PMC11184889
PubMedCentral® Posted Date
6-18-2024
PubMedCentral® Full Text Version
Post-print
Abstract
Background: Aging significantly elevates the risk of developing neurodegenerative diseases. Neuroinflammation is a universal hallmark of neurodegeneration as well as normal brain aging. Which branches of age-related neuroinflammation, and how they precondition the brain toward pathological progression, remain ill-understood. The presence of elevated type I interferon (IFN-I) has been documented in the aged brain, but its role in promoting degenerative processes, such as the loss of neurons in vulnerable regions, has not been studied in depth.
Methods: To comprehend the scope of IFN-I activity in the aging brain, we surveyed IFN-I-responsive reporter mice at multiple ages. We also examined 5- and 24-month-old mice harboring selective ablation of Ifnar1 in microglia to observe the effects of manipulating this pathway during the aging process using bulk RNA sequencing and histological parameters.
Results: We detected age-dependent IFN-I signal escalation in multiple brain cell types from various regions, especially in microglia. Selective ablation of Ifnar1 from microglia in aged mice significantly reduced overall brain IFN-I signature, dampened microglial reactivity, lessened neuronal loss, restored expression of key neuronal genes and pathways, and diminished the accumulation of lipofuscin, a core hallmark of cellular aging in the brain.
Conclusions: Overall, our study demonstrates pervasive IFN-I activity during normal mouse brain aging and reveals a pathogenic, pro-degenerative role played by microglial IFN-I signaling in perpetuating neuroinflammation, neuronal dysfunction, and molecular aggregation. These findings extend the understanding of a principal axis of age-related inflammation in the brain, one likely shared with multiple neurological disorders, and provide a rationale to modulate aberrant immune activation to mitigate neurodegenerative process at all stages.
Keywords
Animals, Aging, Interferon Type I, Mice, Brain, Signal Transduction, Microglia, Receptor, Interferon alpha-beta, Neurons, Interferon, Aging, Neuroinflammation, Microglia, Brain
Published Open-Access
yes
Recommended Citation
Roy, Ethan R; Li, Sanming; Saroukhani, Sepideh; et al., "Fate-Mapping and Functional Dissection Reveal Perilous Influence of Type I Interferon Signaling in Mouse Brain Aging" (2024). Faculty, Staff and Student Publications. 2796.
https://digitalcommons.library.tmc.edu/uthmed_docs/2796