Department of Pharmacology and Toxicology, The Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, USA.
Cardiopulmonary and Immunotoxicology Branch, Public Health and Integrated Toxicology Division, U.S. Environmental Protection Agency, Research Triangle Park, NC, USA.
Brain. 2023 Mar 1;146(3):991-1005. doi: 10.1093/brain/awac113.
The mechanisms underlying how urban air pollution affects Alzheimer's disease (AD) are largely unknown. Ozone (O3) is a reactive gas component of air pollution linked to increased AD risk, but is confined to the respiratory tract after inhalation, implicating the peripheral immune response to air pollution in AD neuropathology. Here, we demonstrate that O3 exposure impaired the ability of microglia, the brain's parenchymal immune cells, to associate with and form a protective barrier around Aβ plaques, leading to augmented dystrophic neurites and increased Aβ plaque load. Spatial proteomic profiling analysis of peri-plaque proteins revealed a microenvironment-specific signature of dysregulated disease-associated microglia protein expression and increased pathogenic molecule levels with O3 exposure. Unexpectedly, 5xFAD mice exhibited an augmented pulmonary cell and humoral immune response to O3, supporting that ongoing neuropathology may regulate the peripheral O3 response. Circulating HMGB1 was one factor upregulated in only 5xFAD mice, and peripheral HMGB1 was separately shown to regulate brain Trem2 mRNA expression. These findings demonstrate a bidirectional lung-brain axis regulating the central and peripheral AD immune response and highlight this interaction as a potential novel therapeutic target in AD.
城市空气污染影响阿尔茨海默病（AD）的机制在很大程度上尚不清楚。臭氧（O3）是空气污染的一种反应性气体成分，与 AD 风险增加有关，但吸入后仅限于呼吸道，这表明空气污染对 AD 神经病理学的外周免疫反应。在这里，我们证明 O3 暴露会损害小胶质细胞（大脑实质免疫细胞）与 Aβ斑块结合并形成保护屏障的能力，导致树突状神经突变形和 Aβ斑块负荷增加。斑块周围蛋白的空间蛋白质组分析揭示了 O3 暴露后与失调疾病相关的小胶质细胞蛋白表达和增加的致病分子水平相关的微环境特异性特征。出乎意料的是，5xFAD 小鼠对 O3 表现出增强的肺细胞和体液免疫反应，支持持续的神经病理学可能调节外周 O3 反应。循环 HMGB1 是仅在 5xFAD 小鼠中上调的一个因素，并且已经表明外周 HMGB1 分别调节大脑 Trem2 mRNA 表达。这些发现表明调节中枢和外周 AD 免疫反应的肺脑双向轴，并强调这种相互作用作为 AD 的潜在新治疗靶点。
