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<p>Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have shown neuroprotective potential, but the mechanisms underlying these effects remain incompletely understood. This study investigated whether semaglutide, a long-acting GLP-1RA, ameliorates AD-like phenotypes in APP/PS1 mice and explored associated changes in neuroinflammatory signaling and blood–brain barrier (BBB) integrity. Eight-month-old amyloid precursor protein/presenilin 1 (APP/PS1) transgenic mice were treated with semaglutide for 8 weeks. Cognitive performance was evaluated using the Morris water maze (MWM). AD-related neuropathology, neuroinflammation-associated protein markers, BBB integrity–related measures, and microglial ultrastructure were assessed using histological, ultrastructural, and molecular approaches. Fecal microbiota composition was profiled by 16&#xa0;S rRNA amplicon sequencing. Semaglutide improved cognitive performance in APP/PS1 mice and was associated with attenuation of neuronal loss–related changes, reduced Aβ deposition, and improved synaptic ultrastructure. Semaglutide also reduced the AD-associated upregulation of inflammasome-/pyroptosis-associated proteins (including NLRP3-related and caspase-11–related markers) and TLR4/NF-κB–related inflammatory signaling proteins, accompanied by attenuation of microglial mitochondrial ultrastructural abnormalities. In addition, semaglutide improved markers of BBB integrity (tight junction proteins and brain albumin levels) and increased BBB-related Aβ clearance proteins (LRP-1 and P-gp). Gut microbiota profiling revealed genus-level differences between WT and APP/PS1 mice without significant changes in α- or β-diversity. Semaglutide was associated with improved cognition and attenuation of AD-like pathology and neuroinflammatory signaling in APP/PS1 mice, accompanied by partial preservation of BBB integrity.</p>

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Semaglutide ameliorates neuroinflammation and cognitive impairment in APP/PS1 mice

  • 期刊论文

  • 发表日期：

    2026年5月13日

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  • Yuan Yuan,
  • Jiawei Zhang,
  • Ziyao Zhang,
  • Yanyu Zhai,
  • Xiao Juan Cheng,
  • Lixia Xue,
  • Fei Zhao,
  • Li Cao,
  • Hongmei Wang

摘要

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have shown neuroprotective potential, but the mechanisms underlying these effects remain incompletely understood. This study investigated whether semaglutide, a long-acting GLP-1RA, ameliorates AD-like phenotypes in APP/PS1 mice and explored associated changes in neuroinflammatory signaling and blood–brain barrier (BBB) integrity. Eight-month-old amyloid precursor protein/presenilin 1 (APP/PS1) transgenic mice were treated with semaglutide for 8 weeks. Cognitive performance was evaluated using the Morris water maze (MWM). AD-related neuropathology, neuroinflammation-associated protein markers, BBB integrity–related measures, and microglial ultrastructure were assessed using histological, ultrastructural, and molecular approaches. Fecal microbiota composition was profiled by 16 S rRNA amplicon sequencing. Semaglutide improved cognitive performance in APP/PS1 mice and was associated with attenuation of neuronal loss–related changes, reduced Aβ deposition, and improved synaptic ultrastructure. Semaglutide also reduced the AD-associated upregulation of inflammasome-/pyroptosis-associated proteins (including NLRP3-related and caspase-11–related markers) and TLR4/NF-κB–related inflammatory signaling proteins, accompanied by attenuation of microglial mitochondrial ultrastructural abnormalities. In addition, semaglutide improved markers of BBB integrity (tight junction proteins and brain albumin levels) and increased BBB-related Aβ clearance proteins (LRP-1 and P-gp). Gut microbiota profiling revealed genus-level differences between WT and APP/PS1 mice without significant changes in α- or β-diversity. Semaglutide was associated with improved cognition and attenuation of AD-like pathology and neuroinflammatory signaling in APP/PS1 mice, accompanied by partial preservation of BBB integrity.