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Background <p>Oxidative stress, neuroinflammation, and cellular senescence interact to drive Alzheimer’s disease (AD) progression. SRS11-92 is a redox-active small molecule with reported cytoprotective effects. This study sought to determine whether SRS11-92 mitigates Aβ-evoked oxidative stress and cellular senescence, and to delineate the underlying mechanism.</p> Methods <p>SH-SY5Y cells were challenged with Aβ<sub>25-35</sub> and pretreated with SRS11-92. Oxidative stress (ROS, MDA, SOD activity, and GSH), inflammatory mediators (TNF-α, IL-1β, and IL-6), senescence markers (SA-β-gal, p53, p16, and p21), and Nrf2/HO-1/NF-κB proteins were quantified. Pathway dependence was assessed using the selective Nrf2 inhibitor ML385. 3xTg-AD mice received SRS11-92 for 6&#xa0;weeks; cognitive function was assessed by novel object recognition, cortical neuronal integrity was assessed by Nissl staining, and cellular senescence in the hippocampus was evaluated by SA-β-gal.</p> Results <p>SRS11-92 attenuated Aβ<sub>25-35</sub>-induced cytotoxicity in a dose-dependent manner in SH-SY5Y cells, reduced ROS and MDA, and restored SOD activity and GSH. It suppressed TNF-α, IL-1β, and IL-6, decreased the percentage of SA-β-gal-positive cells, and downregulated p53, p16, and p21. Mechanistically, SRS11-92 increased total and nuclear Nrf2 and upregulated HO-1, while restricting NF-κB p65 nuclear translocation. ML385 abrogated these molecular and phenotypic benefits, confirming that SRS11-92 acts via the Nrf2 pathway in vitro. In 3xTg-AD mice, SRS11-92 improved cognitive function, partially rescued cortical Nissl-positive neurons, and reduced the hippocampal SA-β-gal-positive burden.</p> Conclusions <p>SRS11-92 exerts significant neuroprotective effects, attributable to reducing stress-induced senescence via activating Nrf2/HO-1 and constraining NF-κB signalling.</p>

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Neuroprotective effects of SRS11-92 against oxidative stress–induced senescence via Nrf2/HO-1/NF-κB in Alzheimer’s disease models

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月6日

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  • Yu Guo,
  • Huan Cao,
  • Chengchao Zuo,
  • Yaqi Huang,
  • Zhongya Gu,
  • Yu Song,
  • Xiang Chen,
  • Qingqing Jiang,
  • Furong Wang

摘要

Background

Oxidative stress, neuroinflammation, and cellular senescence interact to drive Alzheimer’s disease (AD) progression. SRS11-92 is a redox-active small molecule with reported cytoprotective effects. This study sought to determine whether SRS11-92 mitigates Aβ-evoked oxidative stress and cellular senescence, and to delineate the underlying mechanism.

Methods

SH-SY5Y cells were challenged with Aβ25-35 and pretreated with SRS11-92. Oxidative stress (ROS, MDA, SOD activity, and GSH), inflammatory mediators (TNF-α, IL-1β, and IL-6), senescence markers (SA-β-gal, p53, p16, and p21), and Nrf2/HO-1/NF-κB proteins were quantified. Pathway dependence was assessed using the selective Nrf2 inhibitor ML385. 3xTg-AD mice received SRS11-92 for 6 weeks; cognitive function was assessed by novel object recognition, cortical neuronal integrity was assessed by Nissl staining, and cellular senescence in the hippocampus was evaluated by SA-β-gal.

Results

SRS11-92 attenuated Aβ25-35-induced cytotoxicity in a dose-dependent manner in SH-SY5Y cells, reduced ROS and MDA, and restored SOD activity and GSH. It suppressed TNF-α, IL-1β, and IL-6, decreased the percentage of SA-β-gal-positive cells, and downregulated p53, p16, and p21. Mechanistically, SRS11-92 increased total and nuclear Nrf2 and upregulated HO-1, while restricting NF-κB p65 nuclear translocation. ML385 abrogated these molecular and phenotypic benefits, confirming that SRS11-92 acts via the Nrf2 pathway in vitro. In 3xTg-AD mice, SRS11-92 improved cognitive function, partially rescued cortical Nissl-positive neurons, and reduced the hippocampal SA-β-gal-positive burden.

Conclusions

SRS11-92 exerts significant neuroprotective effects, attributable to reducing stress-induced senescence via activating Nrf2/HO-1 and constraining NF-κB signalling.