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

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.