Semaglutide Ameliorates Neuroinflammation Caused by Enterogenous Pyrogen in APP/PS1 Mice

Background and purpose: Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive cognitive dysfunction, which is common in the elderly. In recent years, it has been reported that glucagon-like peptide 1 (GLP-1) analogues have neuroprotective function. However, the mechanism of GLP-1 analogues improving neurological function has not been fully clarified. This study attempts to clarify the mechanism of GLP-1 alleviating AD phenotype. Methods: In this study, a modified once-weekly GLP-1 analogue, Semaglutide, was used to treat 8-month-old amyloid precursor protein / presenilin 1 (APP/PS1) transgenic mice. By means of ethology, molecular biology and 16s rRNA amplicon sequencing, it was confirmed that Semaglutide alleviated the disease phenotype of APP/PS1 mice. Results: GLP-1 improved the behavioral performance of APP/PS1 mice, reduced neuronal damage and aggregation of amyloid-β (Aβ) plaques, and enhanced synaptic plasticity. GLP-1 also attenuated pyroptosis mediated by NOD-like receptor thermal protein domain associated protein 3 (NLRP3), inflammatory reaction mediated by toll-like receptor 4 (TLR4) and mitochondrial damage of microglia as well as improved the structure and function of blood-brain barrier (BBB) in AD mice. Conclusion: GLP-1 may repair the blood-brain barrier to alleviate the central nervous system injury caused by the displacement of pyrogen in gut of AD mice.