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<p>Alzheimer’s disease (AD) is characterized by progressive memory decline and neuronal loss, driven primarily by dysregulated inflammatory signaling. Signal transducer and activator of transcription 6 (STAT6) is a member of the STAT family and has been implicated in the progression of various diseases. This study aimed to investigate whether inhibiting STAT6 and its downstream target, suppressor of cytokine signaling 2 (SOCS2), could mitigate Aβ1-42-induced neuronal injury in both cellular and animal models of AD. AD-like pathology was induced in Sprague–Dawley rats (<i>n</i> = 10 per group) by intracerebral administration of amyloid β1-42 (Aβ1-42). Radial arm maze test, elevated plus maze test, and passive avoidance task were performed to estimate cognitive impairments of AD rats. H&amp;E and TUNEL staining were performed to analyze pathological changes as well as neuron loss and apoptosis. HT-22 neuron cells were exposed to Aβ1-42 to establish an AD-relevant in vitro model. Cell viability and apoptosis were evaluated via CCK-8 and flow cytometry. Bax and Bcl-2 levels were estimated by Western blotting. Reactive oxygen species (ROS) production was measured using the DCFH-DA assay. ChIP and luciferase reporter assays were performed to assess the interaction between STAT6 and SOCS2 promoter. The results showed that&#xa0;STAT6 expression was significantly upregulated in the hippocampus of rats following Aβ1-42 infusion. Silencing of STAT6 alleviated Aβ1-42-induced cognitive impairments in AD rats by significantly reducing neuronal apoptosis (as evidenced by fewer TUNEL-positive cells), attenuating oxidative stress (indicated by reduced MDA levels and restored activities of antioxidant enzymes SOD and GSH-Px), and downregulating SOCS2 levels in vivo. Consistently, in vitro experiments demonstrated that STAT6 knockdown in HT-22 hippocampal neurons markedly inhibited Aβ1-42-triggered apoptosis, intracellular ROS accumulation, and oxidative stress marker dysregulation, whereas overexpressed STAT6 exerted an opposite role. Notably, STAT6 was found to bind to the SOCS2 promoter region. Functionally, SOCS2 overexpression alone accelerated HT-22 cell injury, and critically, it abolished the neuroprotective effects conferred by STAT6 depletion, specifically reversing the suppression of apoptosis and oxidative stress. These findings implicate that the STAT6–SOCS2 axis contributes to AD pathology, and their inhibition exerts neuroprotective effects.</p>

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STAT6-Mediated SOCS2 Alleviates Cognitive Impairments and Neuronal Damage in Alzheimer’s Disease Rat Models and Aβ1-42-Stimulated HT-22 Cells

  • 期刊论文

  • 发表日期：

    2026年1月1日

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  • Yu Liu,
  • Lang Peng,
  • Ming Li,
  • Wenjing Yan,
  • Qingwei Xiang

摘要

Alzheimer’s disease (AD) is characterized by progressive memory decline and neuronal loss, driven primarily by dysregulated inflammatory signaling. Signal transducer and activator of transcription 6 (STAT6) is a member of the STAT family and has been implicated in the progression of various diseases. This study aimed to investigate whether inhibiting STAT6 and its downstream target, suppressor of cytokine signaling 2 (SOCS2), could mitigate Aβ1-42-induced neuronal injury in both cellular and animal models of AD. AD-like pathology was induced in Sprague–Dawley rats (n = 10 per group) by intracerebral administration of amyloid β1-42 (Aβ1-42). Radial arm maze test, elevated plus maze test, and passive avoidance task were performed to estimate cognitive impairments of AD rats. H&E and TUNEL staining were performed to analyze pathological changes as well as neuron loss and apoptosis. HT-22 neuron cells were exposed to Aβ1-42 to establish an AD-relevant in vitro model. Cell viability and apoptosis were evaluated via CCK-8 and flow cytometry. Bax and Bcl-2 levels were estimated by Western blotting. Reactive oxygen species (ROS) production was measured using the DCFH-DA assay. ChIP and luciferase reporter assays were performed to assess the interaction between STAT6 and SOCS2 promoter. The results showed that STAT6 expression was significantly upregulated in the hippocampus of rats following Aβ1-42 infusion. Silencing of STAT6 alleviated Aβ1-42-induced cognitive impairments in AD rats by significantly reducing neuronal apoptosis (as evidenced by fewer TUNEL-positive cells), attenuating oxidative stress (indicated by reduced MDA levels and restored activities of antioxidant enzymes SOD and GSH-Px), and downregulating SOCS2 levels in vivo. Consistently, in vitro experiments demonstrated that STAT6 knockdown in HT-22 hippocampal neurons markedly inhibited Aβ1-42-triggered apoptosis, intracellular ROS accumulation, and oxidative stress marker dysregulation, whereas overexpressed STAT6 exerted an opposite role. Notably, STAT6 was found to bind to the SOCS2 promoter region. Functionally, SOCS2 overexpression alone accelerated HT-22 cell injury, and critically, it abolished the neuroprotective effects conferred by STAT6 depletion, specifically reversing the suppression of apoptosis and oxidative stress. These findings implicate that the STAT6–SOCS2 axis contributes to AD pathology, and their inhibition exerts neuroprotective effects.