Upregulated astrocyte HDAC7 induces Alzheimer-like tau pathologies via deacetylating transcription factor-EB and inhibiting lysosome biogenesis

作者：Jinwang Ye, Suyue Zhong, Huali Wan, Xing Guo, Xuanbao Yao, Qiong Liu, Liming Chen, Jian‐Zhi Wang, Shifeng Xiao · 发表于：Molecular Neurodegeneration · 年份：2025 · DOI：10.1186/s13024-025-00796-2 · 被引用次数：27 · 研究领域：Histone Deacetylase Inhibitors Research、Autophagy in Disease and Therapy、Alzheimer's disease research and treatments

BACKGROUND: Astrocytes, the most abundant glial cell type in the brain, will convert into the reactive state in response to proteotoxic stress such as tau accumulation, a characteristic feature of Alzheimer's disease (AD) and other tauopathies. The formation of reactive astrocytes is partially attributed to the disruption of autophagy lysosomal signaling, and inhibiting of some histone deacetylases (HDACs) has been demonstrated to reduce the molecular and functional characteristics of reactive astrocytes. However, the precise role of autophagy lysosomal signaling in astrocytes that regulates tau pathology remains unclear. METHODS: We investigated the expression of class IIa HDAC7 in astrocytes from AD patients and PS19 mice. PS19 mice were treated with AAVs expressing shRNA for HDAC7 with astrocyte-specific promoter and with a selective class IIa HDAC inhibitor, TMP195, and the effects on tau pathology, gliosis, synaptic plasticity and cognition-related behavioral performance were measured. Tau uptake and degradation assays in cultured astrocytes were utilized to investigate the role of HDAC7 on astrocyte-mediated tau clearance. Immunoprecipitation, immunofluorescence, western blotting, RT-qPCR, mass spectrometric, and luciferase reporter assay were used to identify HDAC7 substrates, modification site and related signaling pathways in astrocyte-tau clearance. We generated a new antibody to clarify the role of HDAC7-mediated signaling in AD patients and PS19 mice. RESULTS: Her...