Neuropharmacology · 2025
GLP-1 receptor agonist semaglutide ameliorates motor deficits and tau pathology in the rTg4510s mouse model.
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Zhang Meng-Wei, Zhou Wan-Yi, Li Xin-Yi, Xu Zhi-Heng, Lin Hua-Mei, Tang Yi-Lin, Zhao Jue, Chen Chen, Liu Feng-Tao, Sun Yi-Min, Zuo Chuan-Tao, Wu Jian-Jun, Wang Jian, Yu Wen-Bo
Аннотация
BACKGROUND: Tauopathies, including Alzheimer's disease, are characterized by progressive neurodegeneration manifesting as motor and cognitive impairments. This study evaluated the therapeutic potential of semaglutide, a clinically approved glucagon-like peptide-1 receptor agonist, in the rTg4510 mouse model of tauopathy.
METHODS: Starting at three months of age, rTg4510 mice and wild-type littermates received semaglutide (0.10 mg kg-1, intraperitoneal) or vehicle (PBS) every other day for 16 weeks. Motor coordination, anxiety-like behavior, spatial working memory, and associative fear memory were assessed using behavioral paradigms. Tau accumulation was monitored via 18F-PM-PBB3 micro-PET/CT imaging. Immunohistochemistry and immunoblot analyses quantified tau pathology, neuronal integrity, and glial activation.
RESULTS: Semaglutide significantly improved motor coordination in rTg4510 mice on the pole test, though not rotarod endurance. While spontaneous locomotion, anxiety-like behaviors, and Y-maze spatial working memory remained unchanged, semaglutide significantly enhanced cue-dependent freezing in fear conditioning, indicating improved associative memory. 18F-PM-PBB3 PET imaging revealed a pronounced reduction in cortical and hippocampal tracer uptake, indicative of reduced tau burden. Immunohistochemistry and Western blotting confirmed significantly decreased cortical phosphorylated tau (AT8) levels. Semaglutide preserved cortical neuronal integrity; however, no hippocampal changes were detected, likely due to minimal baseline neuron loss at this age. Astrocytic (GFAP) and microglial (Iba1) activation remained unaffected.
CONCLUSION: Semaglutide ameliorated domain-specific motor impairments, enhanced associative fear memory, and attenuated cortical tau pathology in rTg4510 mice. These findings highlight therapeutic promise of semaglutide as a disease-modifying agent for tauopathies, justifying further dose-response, mechanistic, and translational studies.
METHODS: Starting at three months of age, rTg4510 mice and wild-type littermates received semaglutide (0.10 mg kg-1, intraperitoneal) or vehicle (PBS) every other day for 16 weeks. Motor coordination, anxiety-like behavior, spatial working memory, and associative fear memory were assessed using behavioral paradigms. Tau accumulation was monitored via 18F-PM-PBB3 micro-PET/CT imaging. Immunohistochemistry and immunoblot analyses quantified tau pathology, neuronal integrity, and glial activation.
RESULTS: Semaglutide significantly improved motor coordination in rTg4510 mice on the pole test, though not rotarod endurance. While spontaneous locomotion, anxiety-like behaviors, and Y-maze spatial working memory remained unchanged, semaglutide significantly enhanced cue-dependent freezing in fear conditioning, indicating improved associative memory. 18F-PM-PBB3 PET imaging revealed a pronounced reduction in cortical and hippocampal tracer uptake, indicative of reduced tau burden. Immunohistochemistry and Western blotting confirmed significantly decreased cortical phosphorylated tau (AT8) levels. Semaglutide preserved cortical neuronal integrity; however, no hippocampal changes were detected, likely due to minimal baseline neuron loss at this age. Astrocytic (GFAP) and microglial (Iba1) activation remained unaffected.
CONCLUSION: Semaglutide ameliorated domain-specific motor impairments, enhanced associative fear memory, and attenuated cortical tau pathology in rTg4510 mice. These findings highlight therapeutic promise of semaglutide as a disease-modifying agent for tauopathies, justifying further dose-response, mechanistic, and translational studies.