Israel Liron L, Braubach Oliver, Shatalova Ekaterina S, Chepurna Oksana, Sharma Sachin, Klymyshyn Dmytro, Galstyan Anna, Chiechi Antonella, Cox Alysia, Herman David, Bliss Bishop, Hasen Irene, Ting Amanda, Arechavala Rebecca, Kleinman Michael T, Patil Rameshwar, Holler Eggehard, Ljubimova Julia Y, Koronyo-Hamaoui Maya, Sun Tao, Black Keith L
Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, CA 90048, United States of America.
Department of Environmental and Occupational Health, University of California, Irvine 92697, United States of America.
Neurobiol Dis. 2023 Oct 15;187:106307. doi: 10.1016/j.nbd.2023.106307. Epub 2023 Sep 20.
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.
空气污染对人类健康构成重大威胁，尽管对其机制的清晰理解仍然难以捉摸。在本研究中，我们试图使用阿尔茨海默病（AD）小鼠模型，更好地了解污染空气中不同大小的颗粒物对AD发展的影响。我们将处于前驱期的转基因阿尔茨海默病小鼠暴露于不同大小的颗粒物（PM）中，以过滤后的清洁空气作为对照。暴露3或6个月后，采集并分析小鼠大脑。RNA测序分析表明，各种PM对大脑转录组有不同影响，且这些影响似乎与PM大小相关。PM暴露后，许多基因和通路受到影响。其中，我们发现无义介导的mRNA衰变途径有强烈激活，与转录、神经发生和生存信号以及血管生成相关的通路有抑制，胶原蛋白有显著下调。尽管我们未检测到任何细胞外Aβ斑块，但免疫染色显示，与清洁空气对照相比，在各种PM暴露条件下，细胞内Aβ1-42和磷酸化Tau水平均升高。NanoString GeoMx分析表明，PM暴露的小鼠大脑中免疫反应有显著激活。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有强烈激活。总体而言，我们的数据表明，暴露于空气中的PM会导致深刻的转录失调并加速阿尔茨海默病相关病理变化。
