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bioRxiv · 10.1101/2024.05.20.595027

Fate-mapping and functional dissection reveal perilous influence of type I interferon signaling in mouse brain aging

Roy, E.·Li, S.·Wang, Y.·Cao, W.
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Abstract

Although aging significantly elevates the risk of developing neurodegenerative diseases, how age-related neuroinflammation preconditions the brain toward pathological progression is ill-understood. To comprehend the scope of type I interferon (IFN-I) activity in the aging brain, we surveyed IFN-I-responsive reporter mice and detected age-dependent signal escalation in multiple brain cell types from various regions. Selective ablation of Ifnar1 from microglia in aged mice significantly reduced overall brain IFN-I signature, dampened microglial reactivity, lessened neuronal loss, and diminished the accumulation of lipofuscin, a core hallmark of cellular aging in the brain. Overall, our study demonstrates pervasive IFN-I activity during normal mouse brain aging and reveals a pathogenic 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, and provide a rationale to modulate aberrant immune activation to mitigate neurodegenerative process at all stages.

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Roy, E., Li, S., Wang, Y., Cao, W.. 2024-05-20. Fate-mapping and functional dissection reveal perilous influence of type I interferon signaling in mouse brain aging. https://doi.org/10.1101/2024.05.20.595027

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