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<p>Astrocyte senescence has been identified as a factor in the progression of Parkinson’s disease (PD) and the onset of age-related cognitive decline. Glucagon-like peptide-1 (GLP-1) has developed into a novel neuroprotective strategy for PD. However, the effects of GLP-1 on astrocyte senescence in PD remain to be elucidated. In our research, we developed an engineered strain of <i>Clostridium butyricum</i>-pMTL007-GLP-1 that continuously expresses GLP-1 and has demonstrated neuroprotective effects in PD. We utilized the Prnp-SNCA*A53T transgenic mouse model to better replicate the degenerative characteristics of PD. Our findings indicated that <i>C. butyricum</i>-GLP-1 reduced misfolded α-synuclein (α-syn), prevented dopaminergic (DAergic) neuron loss, mitigated neuroinflammation, and enhanced motor function impairments in A53T mouse. Additionally, <i>C. butyricum</i>-GLP-1 crossed the blood–brain barrier (BBB) and bound to GLP-1 receptors, reducing the build-up of senescent astrocytes, as evidenced by increased expression of Lamin B1, decreased levels of the senescence biomarker p21, and decreased levels of the pro-inflammatory senescence-associated secretory phenotype (SASP). Moreover, <i>C. butyricum-</i>GLP-1 mitigated oxidative stress-induced senescence by regulating the Nrf2/HO-1 axis and enhancing antioxidant efficacy. 16S rRNA analysis indicated that <i>C. butyricum-</i>GLP-1 strengthened the gastrointestinal barrier, restored gut microbiota homeostasis, and upregulated the abundance of <i>C. butyricum</i>. In summary, the results of this study suggested that <i>C. butyricum</i>-GLP-1 inhibited p53/p21 pathway, mitigated oxidative stress by targeting astrocyte senescence, and regulated gut microbiota, suggesting it may represent a therapeutic approach that brings renewed hope to patients with age-related diseases, such as PD.</p>

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Engineered Clostridium butyricum-pMTL007-GLP-1 Delays Neurodegeneration in Prnp-SNCA*A53T Transgenic Mice Model by Suppressing Astrocyte Senescence

  • 期刊论文

  • 发表日期：

    2025年7月8日

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  • Bin Liao,
  • Leiping Ding,
  • Wenjing Chen,
  • Mengyun Yue,
  • Yun Wang,
  • Daojun Hong,
  • Tingtao Chen,
  • Xin Fang

摘要

Astrocyte senescence has been identified as a factor in the progression of Parkinson’s disease (PD) and the onset of age-related cognitive decline. Glucagon-like peptide-1 (GLP-1) has developed into a novel neuroprotective strategy for PD. However, the effects of GLP-1 on astrocyte senescence in PD remain to be elucidated. In our research, we developed an engineered strain of Clostridium butyricum-pMTL007-GLP-1 that continuously expresses GLP-1 and has demonstrated neuroprotective effects in PD. We utilized the Prnp-SNCA*A53T transgenic mouse model to better replicate the degenerative characteristics of PD. Our findings indicated that C. butyricum-GLP-1 reduced misfolded α-synuclein (α-syn), prevented dopaminergic (DAergic) neuron loss, mitigated neuroinflammation, and enhanced motor function impairments in A53T mouse. Additionally, C. butyricum-GLP-1 crossed the blood–brain barrier (BBB) and bound to GLP-1 receptors, reducing the build-up of senescent astrocytes, as evidenced by increased expression of Lamin B1, decreased levels of the senescence biomarker p21, and decreased levels of the pro-inflammatory senescence-associated secretory phenotype (SASP). Moreover, C. butyricum-GLP-1 mitigated oxidative stress-induced senescence by regulating the Nrf2/HO-1 axis and enhancing antioxidant efficacy. 16S rRNA analysis indicated that C. butyricum-GLP-1 strengthened the gastrointestinal barrier, restored gut microbiota homeostasis, and upregulated the abundance of C. butyricum. In summary, the results of this study suggested that C. butyricum-GLP-1 inhibited p53/p21 pathway, mitigated oxidative stress by targeting astrocyte senescence, and regulated gut microbiota, suggesting it may represent a therapeutic approach that brings renewed hope to patients with age-related diseases, such as PD.