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.