PDF(Pubmed)
Abstract：
Ozone (O3) is an air pollutant associated with Alzheimer\'s disease (AD) risk. The lung-brain axis is implicated in O3-associated glial and amyloid pathobiology; however, the role of disease-associated astrocytes (DAAs) in this process remains unknown.
The O3-induced astrocyte phenotype was characterized in 5xFAD mice by spatial transcriptomics and proteomics. Hmgb1fl/fl LysM-Cre+ mice were used to assess the role of peripheral myeloid cell high mobility group box 1 (HMGB1).
O3 increased astrocyte and plaque numbers, impeded the astrocyte proteomic response to plaque deposition, augmented the DAA transcriptional fingerprint, increased astrocyte-microglia contact, and reduced bronchoalveolar lavage immune cell HMGB1 expression in 5xFAD mice. O3-exposed Hmgb1fl/fl LysM-Cre+ mice exhibited dysregulated DAA mRNA markers.
Astrocytes and peripheral myeloid cells are critical lung-brain axis interactors. HMGB1 loss in peripheral myeloid cells regulates the O3-induced DAA phenotype. These findings demonstrate a mechanism and potential intervention target for air pollution-induced AD pathobiology.
Astrocytes are part of the lung-brain axis, regulating how air pollution affects plaque pathology. Ozone (O3) astrocyte effects are associated with increased plaques and modified by plaque localization. O3 uniquely disrupts the astrocyte transcriptomic and proteomic disease-associated astrocyte (DAA) phenotype in plaque associated astrocytes (PAA). O3 changes the PAA cell contact with microglia and cell-cell communication gene expression. Peripheral myeloid cell high mobility group box 1 regulates O3-induced transcriptomic changes in the DAA phenotype.
The O3-induced astrocyte phenotype was characterized in 5xFAD mice by spatial transcriptomics and proteomics. Hmgb1fl/fl LysM-Cre+ mice were used to assess the role of peripheral myeloid cell high mobility group box 1 (HMGB1).
O3 increased astrocyte and plaque numbers, impeded the astrocyte proteomic response to plaque deposition, augmented the DAA transcriptional fingerprint, increased astrocyte-microglia contact, and reduced bronchoalveolar lavage immune cell HMGB1 expression in 5xFAD mice. O3-exposed Hmgb1fl/fl LysM-Cre+ mice exhibited dysregulated DAA mRNA markers.
Astrocytes and peripheral myeloid cells are critical lung-brain axis interactors. HMGB1 loss in peripheral myeloid cells regulates the O3-induced DAA phenotype. These findings demonstrate a mechanism and potential intervention target for air pollution-induced AD pathobiology.
Astrocytes are part of the lung-brain axis, regulating how air pollution affects plaque pathology. Ozone (O3) astrocyte effects are associated with increased plaques and modified by plaque localization. O3 uniquely disrupts the astrocyte transcriptomic and proteomic disease-associated astrocyte (DAA) phenotype in plaque associated astrocytes (PAA). O3 changes the PAA cell contact with microglia and cell-cell communication gene expression. Peripheral myeloid cell high mobility group box 1 regulates O3-induced transcriptomic changes in the DAA phenotype.
摘要：
背景：臭氧（O3）是与阿尔茨海默病（AD）风险相关的空气污染物。肺脑轴与O3相关的神经胶质和淀粉样蛋白病理生物学有关；然而，疾病相关星形胶质细胞(DAA)在这一过程中的作用尚不清楚.
方法：通过空间转录组学和蛋白质组学在5xFAD小鼠中表征O3诱导的星形胶质细胞表型。Hmgb1fl/flLysM-Cre+小鼠用于评估外周骨髓细胞高迁移率组盒1(HMGB1)的作用。
结果：O3增加星形胶质细胞和斑块数量，阻碍了星形胶质细胞蛋白质组学对斑块沉积的反应，增强了DAA转录指纹，星形胶质细胞-小胶质细胞接触增加，5xFAD小鼠支气管肺泡灌洗免疫细胞HMGB1表达降低。暴露于O3的Hmgb1fl/flLysM-Cre小鼠表现出DAAmRNA标记物失调。
结论：星形胶质细胞和外周骨髓细胞是重要的肺-脑轴相互作用者。外周骨髓细胞中的HMGB1损失调节O3诱导的DAA表型。这些发现证明了空气污染引起的AD病理生物学的机制和潜在的干预目标。
结论：星形胶质细胞是肺脑轴的一部分，调节空气污染如何影响斑块病理。臭氧（O3）星形胶质细胞的作用与斑块增加有关，并通过斑块定位进行修饰。O3独特地破坏斑块相关星形胶质细胞（PAA）中的星形胶质细胞转录组和蛋白质组疾病相关星形胶质细胞（DAA）表型。O3改变PAA细胞与小胶质细胞的接触和细胞间通讯基因的表达。外周骨髓细胞高迁移率组框1调节O3诱导的DAA表型转录组变化。
方法：通过空间转录组学和蛋白质组学在5xFAD小鼠中表征O3诱导的星形胶质细胞表型。Hmgb1fl/flLysM-Cre+小鼠用于评估外周骨髓细胞高迁移率组盒1(HMGB1)的作用。
结果：O3增加星形胶质细胞和斑块数量，阻碍了星形胶质细胞蛋白质组学对斑块沉积的反应，增强了DAA转录指纹，星形胶质细胞-小胶质细胞接触增加，5xFAD小鼠支气管肺泡灌洗免疫细胞HMGB1表达降低。暴露于O3的Hmgb1fl/flLysM-Cre小鼠表现出DAAmRNA标记物失调。
结论：星形胶质细胞和外周骨髓细胞是重要的肺-脑轴相互作用者。外周骨髓细胞中的HMGB1损失调节O3诱导的DAA表型。这些发现证明了空气污染引起的AD病理生物学的机制和潜在的干预目标。
结论：星形胶质细胞是肺脑轴的一部分，调节空气污染如何影响斑块病理。臭氧（O3）星形胶质细胞的作用与斑块增加有关，并通过斑块定位进行修饰。O3独特地破坏斑块相关星形胶质细胞（PAA）中的星形胶质细胞转录组和蛋白质组疾病相关星形胶质细胞（DAA）表型。O3改变PAA细胞与小胶质细胞的接触和细胞间通讯基因的表达。外周骨髓细胞高迁移率组框1调节O3诱导的DAA表型转录组变化。
