Several experimental studies have shown that mesenchymal stem cells are able to induce a therapeutic effect when transplanted into an animal model of Alzheimer’s disease. Neprilysin (NEP) is the main enzyme responsible for the degradation of amyloid (Aβ). In this experimental study, we evaluated whether transplantation of cord blood mesenchymal stem cells genetically modified to express NEP could exert a therapeutic effect in a mouse model of Alzheimer’s disease. Following treatment, a significant improvement in memory was observed in animals that had received both genetically modified and naïve stem cells. In particular, a significant reduction in the expression of Alzheimer-related markers (BACE-1, GFAP, IBA-1) and a significant increase in the expression of the neurotrophic factor BDNF, the neuronal marker NeuN and NEP were observed. These changes were more pronounced in the group of animals treated with genetically modified mesenchymal stem cells than in those that had received unmodified stem cells. Interestingly, no stem cells were detected after transplantation, but extracellular vesicles were identified in the hippocampus of animals that received stem cells (modified and unmodified). The vesicles identified in animals treated with modified stem cells were found to contain more NEP than those from unmodified stem cells. Finally, although no significant difference in cognitive function was found between the groups of animals receiving mesenchymal stem cells, the genetically modified mesenchymal stem cells were found to have a greater ability to induce neurogenesis and reduce inflammation. In conclusion, this study demonstrates that mesenchymal stem cells exert their therapeutic effect in an animal model of Alzheimer’s disease by releasing vesicles and that the increased expression of NEP within the vesicles represents a promising therapeutic option for the treatment of Alzheimer’s disease.

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