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Background and aims <p>Diabetic cognitive impairment (DCI) is a major neurological complication of diabetes, yet its molecular basis remains poorly defined. This study aimed to investigate how the RNA-binding protein TAR DNA-binding protein (TARDBP) regulates neuronal pentraxin 1 (NPTX1) and contributes to DCI pathogenesis.</p> Methods <p>High-glucose (HG)-treated mouse hippocampal HT22 cells and streptozotocin (STZ)-induced DCI mice were used. Gene expression was modulated using small interfering RNA and adeno-associated virus. RNA immunoprecipitation, RNA pull-down assays, and actinomycin D assays were performed to verify TARDBP–NPTX1 interaction and mRNA stability. Cellular viability, apoptosis, mitochondrial function, and behavioral performance were quantitatively assessed.</p> Results <p>Both TARDBP and NPTX1 were significantly upregulated in HG-treated cells and the hippocampus of DCI mice (<i>P</i> &lt; 0.05). Mechanistically, TARDBP directly bound to and enhanced the stability of NPTX1 mRNA, thereby upregulating its expression (<i>P</i> &lt; 0.05). TARDBP knockdown significantly improved cell viability (1.75-fold increase), reduced apoptosis (reduction of 10.4%), increased mitochondrial membrane potential (increase of 9.04%), and decreased ROS levels by 41.7% in vitro (<i>P</i> &lt; 0.05). In DCI mice, AAV-mediated TARDBP silencing enhanced memory performance in the Morris water maze and reduced hippocampal neuronal loss and oxidative stress (<i>P</i> &lt; 0.05). These effects were completely abolished by NPTX1 overexpression (<i>P</i> &lt; 0.05).</p> Conclusion <p>TARDBP aggravates neuronal injury and cognitive dysfunction in diabetes via post-transcriptional stabilization of NPTX1. Targeting the TARDBP–NPTX1 axis may represent a promising therapeutic strategy for diabetic cognitive impairment.</p>

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RNA-binding protein TARDBP enhances NPTX1 stability to induce neuronal injury and diabetic cognitive impairment

  • 期刊论文

  • 发表日期：

    2026年2月6日

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  • GuiTing Liu,
  • XiaoXuan Qi,
  • SiOu Li,
  • XinPing Wang,
  • TingYuan Han,
  • LingJia Cui,
  • HuiYing Yue,
  • Feng Liu,
  • Ying Lin

摘要

Background and aims

Diabetic cognitive impairment (DCI) is a major neurological complication of diabetes, yet its molecular basis remains poorly defined. This study aimed to investigate how the RNA-binding protein TAR DNA-binding protein (TARDBP) regulates neuronal pentraxin 1 (NPTX1) and contributes to DCI pathogenesis.

Methods

High-glucose (HG)-treated mouse hippocampal HT22 cells and streptozotocin (STZ)-induced DCI mice were used. Gene expression was modulated using small interfering RNA and adeno-associated virus. RNA immunoprecipitation, RNA pull-down assays, and actinomycin D assays were performed to verify TARDBP–NPTX1 interaction and mRNA stability. Cellular viability, apoptosis, mitochondrial function, and behavioral performance were quantitatively assessed.

Results

Both TARDBP and NPTX1 were significantly upregulated in HG-treated cells and the hippocampus of DCI mice (P < 0.05). Mechanistically, TARDBP directly bound to and enhanced the stability of NPTX1 mRNA, thereby upregulating its expression (P < 0.05). TARDBP knockdown significantly improved cell viability (1.75-fold increase), reduced apoptosis (reduction of 10.4%), increased mitochondrial membrane potential (increase of 9.04%), and decreased ROS levels by 41.7% in vitro (P < 0.05). In DCI mice, AAV-mediated TARDBP silencing enhanced memory performance in the Morris water maze and reduced hippocampal neuronal loss and oxidative stress (P < 0.05). These effects were completely abolished by NPTX1 overexpression (P < 0.05).

Conclusion

TARDBP aggravates neuronal injury and cognitive dysfunction in diabetes via post-transcriptional stabilization of NPTX1. Targeting the TARDBP–NPTX1 axis may represent a promising therapeutic strategy for diabetic cognitive impairment.