GLP-1 receptor agonist semaglutide ameliorates motor deficits and tau pathology in the rTg4510s mouse model.

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, 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. F-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.