背景:衰老会显著增加患神经退行性疾病的风险。神经炎症是神经变性以及正常脑老化的普遍标志。与年龄相关的神经炎症的哪些分支,以及它们如何使大脑朝着病理进展的方向前进,仍然缺乏理解。升高的I型干扰素(IFN-I)的存在已被证明在老年大脑中,但是它在促进退化过程中的作用,比如脆弱区域的神经元丢失,还没有深入研究。
方法:要了解衰老大脑中IFN-I活动的范围,我们调查了多个年龄的IFN-I反应报告小鼠。我们还检查了5个月和24个月大的小鼠在小胶质细胞中选择性消融Ifnar1,以观察使用大量RNA测序和组织学参数在衰老过程中操纵该途径的影响。
结果:我们在来自不同区域的多种脑细胞类型中检测到年龄依赖性IFN-I信号升高,尤其是小胶质细胞.从老年小鼠的小胶质细胞中选择性消融Ifnar1显着降低了总体脑IFN-I签名,抑制小胶质细胞反应性,减少神经元损失,恢复关键神经元基因和途径的表达,减少了脂褐素的积累,大脑中细胞老化的核心标志。
结论:总体而言,我们的研究表明,在正常小鼠脑老化过程中普遍存在的IFN-I活性,小胶质IFN-I信号在神经炎症中的促变性作用,神经元功能障碍,和分子聚集。这些发现扩展了对大脑中与年龄相关的炎症主轴的理解,一种可能与多种神经系统疾病有关,并提供了调节异常免疫激活以减轻所有阶段的神经退行性过程的基本原理。
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.