APOE4-promoted gliosis and degeneration in tauopathy are ameliorated by pharmacological inhibition of HMGB1 release.

Apolipoprotein E4 (APOE4) is an important driver of Tau pathology, gliosis, and degeneration in Alzheimer's disease (AD). Still, the mechanisms underlying these APOE4-driven pathological effects remain elusive. Here, we report in a tauopathy mouse model that APOE4 promoted the nucleocytoplasmic translocation and release of high-mobility group box 1 (HMGB1) from hippocampal neurons, which correlated with the severity of hippocampal microgliosis and degeneration. Injection of HMGB1 into the hippocampus of young APOE4-tauopathy mice induced considerable and persistent gliosis. Selective removal of neuronal APOE4 reduced HMGB1 translocation and release. Treatment of APOE4-tauopathy mice with HMGB1 inhibitors effectively blocked the intraneuronal translocation and release of HMGB1 and ameliorated the development of APOE4-driven gliosis, Tau pathology, neurodegeneration, and myelin deficits. Single-nucleus RNA sequencing revealed that treatment with HMGB1 inhibitors diminished disease-associated and enriched disease-protective subpopulations of neurons, microglia, and astrocytes in APOE4-tauopathy mice. Thus, HMGB1 inhibitors represent a promising approach for treating APOE4-related AD. [Display omitted] • APOE4 promotes neuronal HMGB1 translocation and release in tauopathy mice • Neuronal APOE4 removal reduces HMGB1 translocation and release in tauopathy mice • Treatment with HMGB1 inhibitors ameliorates APOE4-driven gliosis and AD pathologies • The inhibitor treatment reduces disease-associated neuronal and glial subtypes Nicole Koutsodendris et al. report that, in a tauopathy mouse model, APOE4 promoted intraneuronal translocation and release of HMGB1, which correlated with the severity of microgliosis and neurodegeneration. Treatment of APOE4-tauopathy mice with HMGB1 inhibitors effectively blocked the intraneuronal translocation and release of HMGB1 and ameliorated APOE4-driven Alzheimer's disease pathologies. [ABSTRACT FROM AUTHOR]