CX3CL1 improves neuronal function in mice with Alzheimer’s disease by inhibiting microglial pyroptosis

Du Juan; Lang Hongmei; Yan Na; Huang Changquan; Wang Binyou; Zhao Baoyu; Zhang Xingping

doi:10.13406/j.cnki.cyxb.003360

您当前的位置：

首页 >

文章列表页 >

CX3CL1 improves neuronal function in mice with Alzheimer’s disease by inhibiting microglial pyroptosis

Basic research | 更新时间：2025-10-22

- CX3CL1 improves neuronal function in mice with Alzheimer’s disease by inhibiting microglial pyroptosis
- Journal of Chongqing Medical University Vol. 48, Issue 10, Pages: 1229-1237(2023)
- 作者机构：
  
  成都市第二人民医院全科医疗科，成都 610000
- 作者简介：
- 基金信息：
- DOI：10.13406/j.cnki.cyxb.003360
  CLC： R749.16
- Received：23 August 2023，
  
  Revised：2023-09-17，
  
  Accepted：25 September 2023，
  
  Published：28 October 2023
- 稿件说明：
移动端阅览
杜娟,郎红梅,严娜,等.CX3CL1通过抑制小胶质细胞焦亡改善阿尔茨海默病小鼠的神经元功能[J].重庆医科大学学报,2023,48(10):1229-1237.

Du Juan,Lang Hongmei,Yan Na,et al.CX3CL1 improves neuronal function in mice with Alzheimer’s disease by inhibiting microglial pyroptosis[J].Journal of Chongqing Medical University,2023,48(10):1229-1237.
杜娟,郎红梅,严娜,等.CX3CL1通过抑制小胶质细胞焦亡改善阿尔茨海默病小鼠的神经元功能[J].重庆医科大学学报,2023,48(10):1229-1237. DOI： 10.13406/j.cnki.cyxb.003360.

Du Juan,Lang Hongmei,Yan Na,et al.CX3CL1 improves neuronal function in mice with Alzheimer’s disease by inhibiting microglial pyroptosis[J].Journal of Chongqing Medical University,2023,48(10):1229-1237. DOI： 10.13406/j.cnki.cyxb.003360.

摘要

目的

通过外源性注射趋化因子（C-X3-C基序）配体1（Fractalkine，CX3CL1）探索其对阿尔茨海默病（Alzheimer’s disease，AD）小鼠神经元功能的影响及机制。

方法

采用APP/PS1双转基因小鼠建立AD模型。将小鼠随机分为4组：对照组、AD模型组、AD+PBS溶剂组、AD+CX3CL1组。AD+CX3CL1组颅内给予CX3CL1。AD+PBS溶剂组注射等容积的PBS溶剂。采用旷场实验和Morris水迷宫测试小鼠认知行为，免疫荧光染色、TUNEL染色、尼氏染色、蛋白质印迹和RT-PCR技术对小鼠海马组织进行分析。

结果

①AD小鼠接受CX3CL1注射后增加了移动距离，但没有显著差异（

=0.189）；在水迷宫测试中，AD+CX3CL1组寻找水下平台的移动距离显著缩短（

=0.001）；②AD模型组中GSDMD（Gasdermin D）蛋白和炎症相关蛋白表达显著升高（

0.05），而CX3CL1注射能显著降低这些蛋白的表达水平（

0.05）；③AD模型组的尼氏体数量、突触相关蛋白25 kDa（synaptosomal-associated protein of 25 kDa，SNAP25）、突触后致密区蛋白95（post synaptic density protein 95，PSD95）和囊泡相关膜蛋白1（vesicle-associated membrane protein 1，VAMP1）表达水平显著降低，而CX3CL1组尼氏体数量（

=0.001）和SNAP25、PSD95、VAMP1蛋白的表达增加（

=0.043，

=0.026，

=0.003）。

结论

外源性CX3CL1注射能够通过调节炎症因子和减少细胞焦亡来改善AD小鼠的神经元功能，保护神经元免受损伤。

Abstract

Objective

To investigate the effect of exogenous injection of chemokine C-X3-C-motif ligand 1（CX3CL1） on neuronal function in mice with Alzheimer’s disease（AD） and its mechanism.

Methods

APP/PS1 double transgenic mice were used to establish a model of AD，and the mice were randomly divided into control group，AD model group，AD+PBS group，and AD+CX3CL1 group. The mice in the AD+CX3CL1 group were given intracranial administration of CX3CL1，and those in the AD+PBS group were injected with an equal volume of PBS solvent. The open field test and the Morris water maze test were used to assess the cognitive behavior of mice，and immunofluorescent staining，TUNEL staining，Nissl staining，Western blotting，and RT-PCR were used to analyze hippocampal tissue.

Results

The AD mice receiving CX3CL1 injection showed an increase in movement distance，but without a significant difference（

=0.189）；however，in the water maze test，the AD+CX3CL1 group showed a significant reduction in the movement distance to reach the submerged platform（

=0.001）. The AD model group had significant increases in the expression levels of gasdermin D and inflammation-related

proteins（

0.05），while CX3CL1 injection significantly reduced the expression levels of these proteins（

0.05）. The AD model group had significant reductions in the number of Nissl bodies and the expression levels of （synaptosomal-associated protein of 25 kDa（SNAP25），post synaptic density protein 95（PSD95），and vesicle-associated membrane protein 1（VAMP1），while the CX3CL1 group showed significant increases in the number of Nissl bodies（

=0.001） and the expression levels of SNAP25，PSD95，and VAMP1（

=0.043，0.026，and 0.003）.

Conclusion

Exogenous CX3CL1 injection can improve neuronal function and protect neurons from damage in AD mice by regulating inflammatory factors and reducing pyroptosis.

关键词

Keywords

references

Walsh S ， Merrick R ， Richard E ， et al . Lecanemab for Alzheimer’s disease [J ] . BMJ ， 2022 ， 379 ： 3010 ．

Fan LY ， Mao CY ， Hu XC ， et al . New insights into the pathogenesis of Alzheimer’s disease [J ] . Front Neurol ， 2020 ， 10 ： 1312 ．

Scheltens P ， De Strooper B ， Kivipelto M ， et al . Alzheimer’s disease [J ] . Lancet ， 2021 ， 397 （ 10284 ）： 1577 - 1590 ．

Antignano I ， Liu YX ， Offermann N ， et al . Aging microglia [J ] . Cell Mol Life Sci ， 2023 ， 80 （ 5 ）： 126 ．

Zhang S ， Liu FB ， Li JM ， et al . A 4.7-kDa polysaccharide from Panax ginseng suppresses Aβ pathology via mitophagy activation in cross-species Alzheimer’s disease models [J ] . Biomedecine Pharmacother ， 2023 ， 167 ： 115442 ．

Subbarayan MS ， Joly-Amado A ， Bickford PC ， et al . CX3CL1/CX3CR1 signaling targets for the treatment of neurodegenerative diseases [J ] . Pharmacol Ther ， 2022 ， 231 ： 107989 ．

Mecca C ， Giambanco I ， Donato R ， et al . Microglia and aging：the role of the TREM2-DAP12 and CX3CL1-CX3CR1 axes [J ] . Int J Mol Sci ， 2018 ， 19 （ 1 ）： 318 ．

Zhang JJ ， Liu YF ， Liu XY ， et al . Dynamic changes of CX3CL1/CX3CR1 axis during microglial activation and motor neuron loss in the spinal cord of ALS mouse model [J ] . Transl Neurodegener ， 2018 ， 7 ： 35 ．

Ge YY ， Wang L ， Wang CC ， et al . CX3CL1 inhibits NLRP3 inflammasome-induced microglial pyroptosis and improves neuronal function in mice with experimentally-induced ischemic stroke [J ] . Life Sci ， 2022 ， 300 ： 120564 ．

Perea JR ， Lleó A ， Alcolea D ， et al . Decreased CX3CL1 levels in the cerebrospinal fluid of patients with Alzheimer’s disease [J ] . Front Neurosci ， 2018 ， 12 ： 609 ．

Bolós M ， Llorens-Martín M ， Perea JR ， et al . Absence of CX3CR1 impairs the internalization of tau by microglia [J ] . Mol Neurodegener ， 2017 ， 12 （ 1 ）： 59 ．

Lénárt N ， Brough D ， Dénes Á . Inflammasomes link vascular disease with neuroinflammation and brain disorders [J ] . J Cereb Blood Flow Metab ， 2016 ， 36 （ 10 ）： 1668 - 1685 ．

Lin JW ， Cheng A ， Cheng K ， et al . New insights into the mechanisms of pyroptosis and implications for diabetic kidney disease [J ] . Int J Mol Sci ， 2020 ， 21 （ 19 ）： 7057 ．

Spangenberg EE ， Green KN . Inflammation in Alzheimer’s disease：lessons learned from microglia-depletion models [J ] . Brain Behav Immun ， 2017 ， 61 ： 1 - 11 ．

Dong YF ， Yong VW . Aging microglia：old friends greet new enemies [J ] . Aging ， 2022 ， 14 （ 18 ）： 7190 - 7192 ．

Korbecki J ， Simińska D ， Kojder K ， et al . Fractalkine/CX3CL1 in neoplastic processes [J ] . Int J Mol Sci ， 2020 ， 21 （ 10 ）： 3723 ．

Lauro C ， Chece G ， Monaco L ， et al . Fractalkine modulates microglia metabolism in brain ischemia [J ] . Front Cell Neurosci ， 2019 ， 13 ： 414 ．

Robinson N ， Ganesan R ， Hegedűs C ， et al . Programmed necrotic cell death of macrophages：focus on pyroptosis，necroptosis，and parthanatos [J ] . Redox Biol ， 2019 ， 26 ： 101239 ．

Zhang YY ， Chen X ， Gueydan C ， et al . Plasma membrane changes during programmed cell deaths [J ] . Cell Res ， 2018 ， 28 （ 1 ）： 9 - 21 ．

Paerewijck O ， Lamkanfi M . The human inflammasomes [J ] . Mol Aspects Med ， 2022 ， 88 ： 101100 ．

Wu PJ ， Hung YF ， Liu HY ， et al . Deletion of the inflammasome sensor Aim2 mitigates aβ deposition and microglial activation but increases inflammatory cytokine expression in an alzheimer disease mouse model [J ] . Neuroimmunomodulation ， 2017 ， 24 （ 1 ）： 29 - 39 ．

Liu ZH ， Wang CP ， Rathkey JK ， et al . Structures of the gasdermin D C-terminal domains reveal mechanisms of autoinhibition [J ] . Structure ， 2018 ， 26 （ 5 ）： 778 - 784 .

Leu WJ ， Chen JC ， Guh JH . Extract from Plectranthus amboinicus inhibit maturation and release of interleukin 1β through inhibition of NF-κB nuclear translocation and NLRP3 inflammasome activation [J ] . Front Pharmacol ， 2019 ， 10 ： 573 ．

Mangan MSJ ， Olhava EJ ， Roush WR ， et al . Targeting the NLRP3 inflammasome in inflammatory diseases [J ] . Nat Rev Drug Discov ， 2018 ， 17 （ 9 ）： 688 ．

Cao RP ， Fang D ， Wang JH ， et al . ALDH2 overexpression alleviates high glucose-induced cardiotoxicity by inhibiting NLRP3 inflammasome activation [J ] . J Diabetes Res ， 2019 ， 2019 ： 4857921 ．

Rajendran L ， Paolicelli RC . Microglia-mediated synapse loss in Alzheimer’s disease [J ] . J Neurosci ， 2018 ， 38 （ 12 ）： 2911 - 2919 ．

Li P ， He YF ， Yang Q ， et al . NEK7 inhibition attenuates Aβ 42 -induced cognitive impairment by regulating TLR4/NF-κB and the NLRP3 inflammasome in mice [J ] . J Clin Biochem Nutr ， 2023 ， 73 （ 2 ）： 145 - 153 ．

Zhang PF ， Hu H ， Tan L ， et al . Microglia biomarkers in Alzheimer’s disease [J ] . Mol Neurobiol ， 2021 ， 58 （ 7 ）： 3388 - 3404 ．

Views

下载量

CSCD

Alert me when the article has been cited

提交

Tools

Publicity Resources

Recommendations for the clinical use of anti-amyloid-β monoclonal antibody for Alzheimer’s disease（2025）

Research advances in triggering receptor expressed on myeloid cells 2 in the pathogenesis of Alzheimer’s disease

Research advances in the pathogenesis and pathophysiological manifestations of interstitial cystitis caused by urothelial cell pyroptosis

Research advances in clinical subtypes of Alzheimer’s disease based on clinical manifestations and pathological features

Effect of voluntary running exercise on oligodendrocytes in the medial prefrontal cortex of APP/PS1 mice

Related Author

Xiao Jinwen

Ren Rujing

Li Binyin

Wang Jintao

Geng Jieli

Cao Wenwei

Song Yaying

Wang Hualong

Related Institution

Department of Neurology， Fujian Medical University Union Hospital

Department of Neurology，Renji Hospital，Shanghai Jiao Tong University School of Medicine

Department of Neurology and Institute of Neurology，Ruijin Hospital，Shanghai Jiao Tong University School of Medicine

Department of Radiology，Shanghai East Hospital，Tongji University School of Medicine

Department of Neurology，First Affiliated Hospital of Zhejiang University School of Medicine

⁰