Preconditioning adipose-derived mesenchymal stem cells with dimethyl fumarate promotes their therapeutic efficacy in the brain tissues of rats with Alzheimer's disease.

ABSTRACT

AIM: Transplantation of mesenchymal stem cell (MSC) has been suggested to be a promising method for treating neurodegenerative conditions, including Alzheimer's disease (AD). However, the poor survival rate of transplanted MSCs has limited their therapeutic application. This study aimed to evaluate whether preconditioning MSCs with dimethyl fumarate (DMF), a Nrf2 inducer, could enhance MSC therapeutic efficacy in an amyloid-ß (Aß1-42)-induced AD rat model. METHODS: The survival and antioxidant capacity of MSCs treated with DMF were assessed in vitro. Aß1-42 intrahippocampal injection was used to create a rat model of AD. Following the transplantation of MSCs preconditioned with DMF and using the Morris blue maze test, spatial learning and memory were assessed. Using RT-qPCR, we evaluated the gene expression related to apoptosis and neurotrophins in the hippocampus region. RESULTS: Treatment with DMF enhanced cell survival and Nrf2 protein expression in MSCs in vitro. Preconditioning with DMF also enhanced the efficacy of transplanted MSCs in rescuing learning and spatial memory deficits in Aß-AD rats. Besides, DMF preconditioning enhanced the neuroprotective effect of transplanted MSCs in the hippocampus of rats treated with Aß1-42 by decreasing the expression of apoptotic markers (Bax, caspase 3, and cytochrome c), and elevating the expression of the anti-apoptotic marker Bcl2 and neurotrophins, including BDNF and NGF. CONCLUSION: Preconditioning MSCs with DMF boosted the therapeutic efficacy of these cells; therefore, it could serve as a targeted strategy for increasing the therapeutic efficacy of MSCs in treating neurodegenerative disorders, including AD.