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

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.

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.

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.

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.