Tideglusib improves novel object recognition memory in the preclinical DBA/2J mdx mouse model of Duchenne muscular dystrophy

Introduction Duchenne muscular dystrophy (DMD) is a severe X-linked neuromuscular disorder characterized by progressive muscle wasting. Approximately 1 in 3 DMD patients experience cognitive dysfunction, with research suggesting an Alzheimer’s disease (AD)-like pathology. We have previously shown that treatment with the glycogen synthase kinase 3β (GSK3) inhibitor, tideglusib, improves muscle quality, function, and insulin sensitivity in the DBA/2J (D2) mdx mouse model of DMD. In this brief follow-up study, we report the effects of tideglusib treatment on cognitive function. Methods Male D2 WT and mdx mice were purchased from Jackson Laboratories. Mice were separated into the following groups: (1) WT, (2) mdx -vehicle, and (3) mdx -tideglusib (10 mg/kg/day via oral gavage for 4 weeks). A novel object recognition test was performed to assess recognition memory. Hippocampus and serum samples were collected for BACE1 activity assays, amyloid beta (Aβ) ELISAs, and western blotting. Results Compared to vehicle-treated mdx mice, tideglusib-treated mdx mice demonstrated improved recognition memory. These changes to recognition memory were accompanied by greater expression of beta-catenin, an indirect downstream marker of GSK3 inhibition. While there were no changes in BACE1 activity, tideglusib-treated mdx mice had higher concentrations of Aβ in the serum and lower protein levels of receptor of advanced glycation end products. Discussion The results from this brief follow-up study offer preliminary support for tideglusib as a treatment for both muscle and brain impairments in mdx mice, potentially improving cognitive function through enhanced vascular Aβ clearance.