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

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. 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. 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. 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. Mice of various genotypes were aged to stated time points and harvested. Bulk cortical tissues were used for RNA-seq analysis.衰老会显著提升神经退行性疾病的发病风险。神经炎症（Neuroinflammation）是神经退行性变与正常大脑衰老的共同标志性特征。 目前，衰老相关神经炎症包含哪些亚型，以及它们如何使大脑预先易发生病理进展，仍未被充分阐明。衰老大脑中已被报道存在升高的I型干扰素（type I interferon, IFN-I）水平，但其在促进退行性进程（如易感区域神经元丢失）中的作用尚未得到深入研究。 为明确衰老大脑中IFN-I活性的作用范围，我们对多个年龄阶段的IFN-I响应性报告基因小鼠进行了系统性观测。 我们还对5月龄与24月龄的小胶质细胞（microglia）特异性敲除Ifnar1的小鼠开展研究，通过批量RNA测序（bulk RNA sequencing）与组织学指标，观测该通路在衰老过程中被调控后的效应。 我们观测到，大脑多个区域的多种细胞类型中均存在年龄依赖性的IFN-I信号上调，尤以小胶质细胞最为显著。 老年小鼠小胶质细胞中Ifnar1的特异性敲除，显著降低了大脑整体的IFN-I特征谱，抑制了小胶质细胞活化，减少了神经元丢失，恢复了关键神经元基因与通路的表达，并减少了脂褐素（lipofuscin）的蓄积——脂褐素是大脑细胞衰老的核心标志性特征。 综上，本研究证实了正常小鼠大脑衰老过程中存在广泛的IFN-I活性，并揭示了小胶质细胞IFN-I信号通路在持续加剧神经炎症、神经元功能障碍与分子聚集过程中的致病性促退行作用。 本研究结果拓展了我们对大脑中衰老相关炎症核心通路的认知，该通路很可能与多种神经系统疾病共享相关机制，并为通过调控异常免疫激活以在全阶段缓解神经退行性进程提供了理论依据。 将不同基因型的小鼠饲养至指定月龄后进行取材，取大脑皮层组织进行批量RNA测序分析。