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

ABSTRACT: 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. In this study, we demonstrated in a tauopathy mouse model that APOE4 promoted the nucleo-cytoplasmic 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 the nucleo-cytoplasmic translocation and release of HMGB1. Therapeutic treatment of APOE4-tauopathy mice with HMGB1 inhibitors effectively blocked the intraneuronal translocation and release of HMGB1 and ameliorated the development of prominent APOE4-driven AD pathologies, including 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE242153 | GEO | 2023/09/01

REPOSITORIES: GEO

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Neuronal APOE4 removal strongly protects against Tau-mediated gliosis, neurodegeneration, and myelin deficits

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