Subcutaneous transplantation of mesenchymal stem cell spheroids ameliorates cognitive deficits in Alzheimer's disease

BackgroundMesenchymal stem cell (MSC)-based therapy has emerged as a promising alternative treatment for Alzheimer's disease (AD) but is limited by low cell survival rates and complex handling.ObjectiveThe present study explored the therapeutic potential of subcutaneous transplantation of MSC spheroids in a mouse AD model.MethodsWe prepared uniform size MSC spheroids with good stemness properties, and performed three consecutive subcutaneous treatments with MSC spheroids on early-stage AD APP/PS1 mice (6 months old), with each injection administered one month apart. Following treatment, behavioral experiments were conducted to evaluate learning and cognitive functions. Additionally, positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) were utilized to assess cerebral glucose metabolism and neuronal functional connectivity. Subsequently, brain tissue sections were prepared and stained to evaluate amyloid plaque deposition, levels of inflammation, and other pathological changes.ResultsAPP/PS1 mice treated with MSC spheroids demonstrated better performance in cognitive behavioral tests compared to the AD model group. Imaging studies showed that brain glucose metabolism was higher in the MSC spheroids-treated group than in the AD model group, with enhanced functional brain connectivity. Moreover, pathological analysis revealed that MSC spheroids treatment resulted in a reduced amyloid-β plaque burden and attenuated inflammatory phenotypes in AD mice. MSC spheroids also protected neurons from apoptosis and restored synaptic plasticity.ConclusionsOur study suggests that subcutaneous transplantation of MSC spheroids reduced key pathological changes in AD by improving brain glucose metabolism and alleviating inflammation.