HDAC7 acts as an astrocytic mediator of Aβ pathology that directly engages IKK to drive astrocyte neurotoxicity and neurodegeneration in Alzheimer's disease.

Overview

1. Brain Disease and Big Data Research Institute, College of Life Sciences and Oceanography, Shenzhen University,Shenzhen, 518060 Guangdong China
2. Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions,Shenzhen, 518055 China
3. Department of Pathophysiology, School of Basic Medicine, Key Laboratory of Ministry of Education of China and Hubei Province for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology,Wuhan, 430030 China
4. Department of Laboratory Medicine, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People’s Hospital,Shenzhen, 518035 China
5. School of Pharmacy, Shenzhen University Medical School, Shenzhen University,Shenzhen, 518055 China

Abstract

Background: Astrocytes undergo reactive transformations in response to pathological stimuli and play a critical role in neuronal loss associated with Alzheimer’s disease (AD). However, the intrinsic mechanisms through which astrocytes detect amyloid-β (Aβ) pathology and develop neurotoxic properties remain inadequately understood. The dysregulation of class IIa Histone deacetylases (HDACs) has been implicated in astrocyte dysfunction under pathological conditions. This study aims to elucidate the role of HDAC7 as an astrocytic mediator of Aβ that drives the formation of neurotoxic reactive astrocytes, and to propose HDAC7 as a potential therapeutic target for mitigating neuronal loss and cognitive deficits in AD.

Methods: We examined HDAC7 expression in APP/PS1 mice of varying ages using RT-qPCR, Western blotting, and immunostaining analysis. Astrocyte-specific HDAC7 overexpression and knockdown were achieved through adeno-associated virus (AAV) delivery (GfaABC1D promoter) in wild-type (WT) and APP/PS1 mice, followed by behavioral tests, immunostaining, RT-qPCR, and RNA-seq. Mechanistic studies were conducted using primary astrocytes derived from WT and Hdac7flx/flx mice, employing co-immunoprecipitation, Western blotting, and neuron viability assays. Pharmacological inhibition of HDAC7 in APP/PS1 mice was performed via intraperitoneal injection of TMP195, and the effects on neurotoxic reactive astrocytes, neuronal and synaptic loss, and behavioral performance were measured.

Results: HDAC7 was selectively upregulated in plaque-adjacent astrocytes in APP/PS1 mice. Overexpression of HDAC7 specifically in astrocytes was sufficient to induce a neurotoxic transcriptional profile, neuronal loss, and cognitive deficits in both WT and young APP/PS1 mice. Mechanistically, upon Aβ stimulation, the upregulated HDAC7 directly interacted with and deacetylated IKKα and IKKβ, resulting in the activation of IKK, translocation of NF-κB to the nucleus, and subsequent expression of neurotoxic genes. This neurotoxic conversion was dependent on IKK activity, as IKK inhibition nullified the effects in astrocytes overexpressing HDAC7. Conversely, astrocytic HDAC7 knockdown or treatment with TMP195 attenuated IKK-NF-κB signaling, reduced the presence of neurotoxic reactive astrocytes, and rescued neurodegeneration and cognitive deficits in APP/PS1 mice.

Conclusions: HDAC7 acts as an intrinsic effector within astrocytes, responding to Aβ pathology and converting astrocytes into a neurotoxic state through direct interaction with IKK. Targeting HDAC7 presents a promising strategy for astrocyte-directed therapeutic interventions in Alzheimer’s disease.

Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s13195-026-02121-5.

Reproduced under the paper's license (CC BY), from the paper cited above.

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• figshare:33421650, at figshare; found in DataCite

Data availability

All data generated during this study and supporting the present results are available from the corresponding author upon reasonable request.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 9 authors, 6 keywords, 12 MeSH terms, 5 funders, 60 references.

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This paper

Ye, J., Deng, Y., Zhang, B., Li, C., Guo, X., Yue, R., Wan, H., Hao, Y., & Xiao, S. (2026). HDAC7 acts as an astrocytic mediator of Aβ pathology that directly engages IKK to drive astrocyte neurotoxicity and neurodegeneration in Alzheimer's disease. Alzheimer's research & therapy, 18(1), 196. https://doi.org/10.1186/s13195-026-02121-5

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