Academic Journal
Upregulated astrocyte HDAC7 induces Alzheimer-like tau pathologies via deacetylating transcription factor-EB and inhibiting lysosome biogenesis
| Title: | Upregulated astrocyte HDAC7 induces Alzheimer-like tau pathologies via deacetylating transcription factor-EB and inhibiting lysosome biogenesis |
|---|---|
| Authors: | Jinwang Ye, Suyue Zhong, Huali Wan, Xing Guo, Xuanbao Yao, Qiong Liu, Liming Chen, Jian-Zhi Wang, Shifeng Xiao |
| Source: | Molecular Neurodegeneration, Vol 20, Iss 1, Pp 1-23 (2025) |
| Publisher Information: | BMC, 2025. |
| Publication Year: | 2025 |
| Collection: | LCC:Neurology. Diseases of the nervous system LCC:Geriatrics |
| Subject Terms: | HDAC7, TFEB, Astrocytes, Lysosomal biogenesis, Tau pathology, Neurology. Diseases of the nervous system, RC346-429, Geriatrics, RC952-954.6 |
| More Details: | Abstract 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 Here, we found that the level of histone deacetylase 7 (HDAC7) was remarkably increased in the astrocytes of AD patients and P301S tau transgenic (PS19) mice. Genetic or pharmacological inhibition of HDAC7 effectively enhanced astrocytic clearance of tau with improved cognitive functions in PS19 mice. HDAC7 could modulate astrocytic uptake and lysosomal degradation of tau proteins through a transcriptional factor EB (TFEB) acetylation-dependent manner. Specifically, deacetylation of TFEB at K310 site by HDAC7 prevented TFEB nuclear translocation with reduced lysosomal biogenesis and tau clearance in astrocytes, whereas inhibiting HDAC7 restored astrocytic TFEB acetylation level at K310 with improved tau pathology and cognitive functions in PS19 mice. Conclusions Our findings suggest that upregulation of HDAC7 induces AD-like tau pathologies via deacetylating TFEB and inhibiting lysosomal biogenesis in astrocytes, and downregulating HDAC7-TFEB signaling is promising for arresting AD and other tauopathies. |
| Document Type: | article |
| File Description: | electronic resource |
| Language: | English |
| ISSN: | 1750-1326 |
| Relation: | https://doaj.org/toc/1750-1326 |
| DOI: | 10.1186/s13024-025-00796-2 |
| Access URL: | https://doaj.org/article/d69d504fdac046fb90f21578793b6eea |
| Accession Number: | edsdoj.69d504fdac046fb90f21578793b6eea |
| Database: | Directory of Open Access Journals |
| Full text is not displayed to guests. | Login for full access. |
| ISSN: | 17501326 |
|---|---|
| DOI: | 10.1186/s13024-025-00796-2 |
| Published in: | Molecular Neurodegeneration |
| Language: | English |