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

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  Hdac7 flx/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.