Scholarlink

Background <p>Vascular dementia is a common cognitive disorder that is often triggered by neuroinflammatory responses caused by cerebrovascular injury, which further exacerbates the progression of the disease. Microglia play an important role in neuroinflammation, and the signalling pathway within them may affect the progression of the disease. The role of SHP2 (Src homology protein-tyrosine phosphatase 2), a key signaling molecule, in microglia during VD remains unclear. This study&#xa0;aimed to investigate&#xa0;the effect and underlying mechanism of microglial SHP2 on the progression of vascular dementia.</p> Methods <p>Bioinformatics analysis was employed to identify genes specifically expressed in vascular dementia. A vascular dementia (VD) model was established in male Wistar rats through bilateral carotid artery ligation. A randomized and double-blind study design was implemented throughout the experiments. Behavioral changes in the rats were assessed using the Morris water maze and open field tests. Pathological conditions in the hippocampal CA1 region were examined via HE staining, while immunohistochemical staining was utilized to detect p-SHP2 expression. Western blot, RT-qPCR, and ELISA were conducted to measure the expression levels of p-Src, p-FAK, p-JNK, p-NF-κB, NOX4, P53, PU. 1, IRF8, NLRP3, NLRC4, αvβ3 integrin, IL-1β, IFNα, IFNβ, IL-18, and β-amyloid in microglial BV2 cells. Angiogenesis assays were performed to evaluate the angiogenic capacity of BV2 cells.</p> Results <p>SHP2 exhibited specific low expression in vascular dementia. It enhanced the learning and memory abilities of rats with vascular dementia and mitigated brain tissue damage caused by the disease. Inhibition of SHP2 within microglia upregulated the expression of p-Src, p-FAK, p-JNK, p-NF-κB, NOX4, P53, PU. 1, IRF8, NLRP3, NLRC4, αvβ3 integrin, IL-1β, IFNα, IFNβ, IL-18, and β-Amyloid. However, administration of the FAK and Src inhibitor SU6656 abolished the effects of SHP2 inhibition, leading to suppressed expression of the aforementioned proteins. Additionally, SHP2 was shown to inhibit the angiogenic capacity of BV2 cells.</p> Conclusions <p>Our findings&#xa0;suggest that&#xa0;SHP2 within microglia&#xa0;may&#xa0;inhibit the progression of vascular dementia by suppressing the FAK/Src/PU. 1/IRF8 pathway-mediated neuroinflammatory response. Targeting SHP2 could represent a potential therapeutic strategy for VD.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

SHP2 in microglia attenuates neuroinflammation and cognitive deficits in vascular dementia by modulating the FAK/Src/PU. 1/IRF8 pathway

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年3月31日

查看全文
  • Yanli Jia,
  • Yanyan Ren,
  • Yunmei Yu,
  • Fangming Dong,
  • Minxia Geng,
  • Rongfang Feng

摘要

Background

Vascular dementia is a common cognitive disorder that is often triggered by neuroinflammatory responses caused by cerebrovascular injury, which further exacerbates the progression of the disease. Microglia play an important role in neuroinflammation, and the signalling pathway within them may affect the progression of the disease. The role of SHP2 (Src homology protein-tyrosine phosphatase 2), a key signaling molecule, in microglia during VD remains unclear. This study aimed to investigate the effect and underlying mechanism of microglial SHP2 on the progression of vascular dementia.

Methods

Bioinformatics analysis was employed to identify genes specifically expressed in vascular dementia. A vascular dementia (VD) model was established in male Wistar rats through bilateral carotid artery ligation. A randomized and double-blind study design was implemented throughout the experiments. Behavioral changes in the rats were assessed using the Morris water maze and open field tests. Pathological conditions in the hippocampal CA1 region were examined via HE staining, while immunohistochemical staining was utilized to detect p-SHP2 expression. Western blot, RT-qPCR, and ELISA were conducted to measure the expression levels of p-Src, p-FAK, p-JNK, p-NF-κB, NOX4, P53, PU. 1, IRF8, NLRP3, NLRC4, αvβ3 integrin, IL-1β, IFNα, IFNβ, IL-18, and β-amyloid in microglial BV2 cells. Angiogenesis assays were performed to evaluate the angiogenic capacity of BV2 cells.

Results

SHP2 exhibited specific low expression in vascular dementia. It enhanced the learning and memory abilities of rats with vascular dementia and mitigated brain tissue damage caused by the disease. Inhibition of SHP2 within microglia upregulated the expression of p-Src, p-FAK, p-JNK, p-NF-κB, NOX4, P53, PU. 1, IRF8, NLRP3, NLRC4, αvβ3 integrin, IL-1β, IFNα, IFNβ, IL-18, and β-Amyloid. However, administration of the FAK and Src inhibitor SU6656 abolished the effects of SHP2 inhibition, leading to suppressed expression of the aforementioned proteins. Additionally, SHP2 was shown to inhibit the angiogenic capacity of BV2 cells.

Conclusions

Our findings suggest that SHP2 within microglia may inhibit the progression of vascular dementia by suppressing the FAK/Src/PU. 1/IRF8 pathway-mediated neuroinflammatory response. Targeting SHP2 could represent a potential therapeutic strategy for VD.