Peripheral HMGB1 is linked to O3 pathology of disease‐associated astrocytes and amyloid

Abstract INTRODUCTION Ozone (O 3 ) is an air pollutant associated with Alzheimer's disease (AD) risk. The lung–brain axis is implicated in O 3 ‐associated glial and amyloid pathobiology; however, the role of disease‐associated astrocytes (DAAs) in this process remains unknown. METHODS The O 3 ‐induced astrocyte phenotype was characterized in 5xFAD mice by spatial transcriptomics and proteomics. Hmgb1 fl/fl LysM ‐Cre + mice were used to assess the role of peripheral myeloid cell high mobility group box 1 (HMGB1). RESULTS O 3 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. O 3 ‐exposed Hmgb1 fl/fl LysM ‐Cre + mice exhibited dysregulated DAA mRNA markers. DISCUSSION Astrocytes and peripheral myeloid cells are critical lung–brain axis interactors. HMGB1 loss in peripheral myeloid cells regulates the O 3 ‐induced DAA phenotype. These findings demonstrate a mechanism and potential intervention target for air pollution–induced AD pathobiology. Highlights Astrocytes are part of the lung–brain axis, regulating how air pollution affects plaque pathology. Ozone (O 3 ) astrocyte effects are associated with increased plaques and modified by plaque localization. O 3 uniquely disrupts the astrocyte transcriptomic and proteomic disease‐associated astrocyte (DAA) phenotype in plaque associated astrocytes (PAA). O 3 changes the PAA cell contact with microglia and cell–cell communication gene expression. Peripheral myeloid cell high mobility group box 1 regulates O 3 ‐induced transcriptomic changes in the DAA phenotype.