HMGB1 is a nuclear protein widely recognized as a critical factor in glial cell activation.39 Under pathological conditions, HMGB1 translocates from the nucleus to the cytoplasm of stressed or dying cells and is then released to act as a proinflammatory DAMP to activate glial cells.36,38,44 Since gliosis is one of the earliest pathological manifestations in the PS19 tauopathy mouse model50 and APOE4 promotes gliosis in this same mouse model (Figures S1H–S1K and S2E–S2H), we investigated if APOE4 affects the nucleocytoplasmic translocation of HMGB1 that can trigger glial response. Here, APOE is linked to tauopathy.