空气污染对人类健康构成重大威胁，但其机制尚未完全清楚。在本研究中，我们试图通过使用AD小鼠模型，更好地理解来自污染空气中不同粒径颗粒物对阿尔茨海默病（AD）发展的影响。我们将转基因阿尔茨海默病小鼠在其前驱阶段暴露于不同粒径颗粒物（PM），其中过滤的清洁空气作为对照。暴露3或6个月后，收获小鼠的大脑进行分析。RNA-seq分析显示不同颗粒物对大脑转录组有差异影响，这些影响似乎与颗粒物大小相关。在颗粒物暴露后，许多基因和通路受到影响。其中，我们发现mRNA诱导性剪切调控途径强烈活化，与转录、神经发生和生存信号以及血管生成相关的通路受抑制，胶原蛋白显著下调。虽然我们没有检测到任何细胞外Aβ斑块，免疫染色显示与清洁空气对照相比，各种粒径颗粒物暴露条件下细胞内Aβ1-42和磷酸化Tau水平均增加。NanoString GeoMx分析展示了暴露于颗粒物的小鼠脑中免疫应答的显著活化。令人惊讶的是，我们的数据还表明包括RB1、CDKN1A/p21和CDKN2A/p16在内的各种肿瘤抑制因子的强烈活化。总的来说，我们的数据表明，暴露于空气中的颗粒物会引起深度转录失调并加速阿尔茨海默病相关病理变化。© 2023版权归Elsevier Inc所有。

Air pollution poses a significant threat to human health, though a clear understanding of its mechanism remains elusive. In this study, we sought to better understand the effects of various sized particulate matter from polluted air on Alzheimer's disease (AD) development using an AD mouse model. We exposed transgenic Alzheimer's mice in their prodromic stage to different sized particulate matter (PM), with filtered clean air as control. After 3 or 6 months of exposure, mouse brains were harvested and analyzed. RNA-seq analysis showed that various PM have differential effects on the brain transcriptome, and these effects seemed to correlate with PM size. Many genes and pathways were affected after PM exposure. Among them, we found a strong activation in mRNA Nonsense Mediated Decay pathway, an inhibition in pathways related to transcription, neurogenesis and survival signaling as well as angiogenesis, and a dramatic downregulation of collagens. Although we did not detect any extracellular Aβ plaques, immunostaining revealed that both intracellular Aβ1-42 and phospho-Tau levels were increased in various PM exposure conditions compared to the clean air control. NanoString GeoMx analysis demonstrated a remarkable activation of immune responses in the PM exposed mouse brain. Surprisingly, our data also indicated a strong activation of various tumor suppressors including RB1, CDKN1A/p21 and CDKN2A/p16. Collectively, our data demonstrated that exposure to airborne PM caused a profound transcriptional dysregulation and accelerated Alzheimer's-related pathology.Copyright © 2023. Published by Elsevier Inc.