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

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. Hmgb1^fl/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 Hmgb1^fl/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.