1. APOE4-promoted gliosis and degeneration in tauopathy are ameliorated by pharmacological inhibition of HMGB1 release.
- Author
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Koutsodendris, Nicole, Blumenfeld, Jessica, Agrawal, Ayushi, Traglia, Michela, Yip, Oscar, Rao, Antara, Kim, Min Joo, Nelson, Maxine R., Wang, Yung-Hua, Grone, Brian, Hao, Yanxia, Thomas, Reuben, Zilberter, Misha, Yoon, Seo Yeon, Arriola, Patrick, and Huang, Yadong
- 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. 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]
- Published
- 2023
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