Therapeutic Effects of Transplantation of As-MiR-937-Expressing Mesenchymal Stem Cells in Murine Model of Alzheimer's Disease.

BACKGROUND/AIMS: Alzheimer's disease (AD) is one of the most common dementias among aged people, and is clinically characterized by progressive memory loss, behavioral and learning dysfunction and cognitive deficits. So far, this is no cure for AD. A therapeutic effect of transplantation of mesenchymal stem cells (MSCs) into murine model of AD has been reported, but remains to be further improved. Brn-4 is a transcription factor that plays a critical role in neuronal development, whereas the effects of Brn-4 overexpression in transplanted MSCs on AD are unknown.

METHODS

MSCs were isolated from mouse bone marrow and induced to overexpress antisense of miRNA-937 (as-miR-937) through adeno-associated virus (AAV)-mediated transduction, and purified by flow cytometry based on expression of a GFP co-transgene in the cells. The Brn-4 levels in mouse MSCs were examined in miR-937-modified MSCs by RT-qPCR and by Western blot. These miR-937-modified MSCs were then transplanted into an APP/PS1 transgenic AD model in mice. The effects of saline control, MSCs and asmiR-937 MSCs on AD mice were examined by deposition of amyloid-beta peptide aggregates (Aβ), social recognition test (SR), Plus-Maze Discriminative Avoidance Task (PM-DAT) and the levels of Brain-derived neurotrophic factor (BDNF) in the mouse brain.

RESULTS

MSCs expressed high levels of Brn-4 transcripts but low levels of Brn-4 protein. Poor protein vs mRNA levels of Brn-4 in MSCs appeared to result from the presence of high levels of miR-937 in MSCs. miR-937 inhibited translation of Brn-4 mRNA through binding to the 3'-UTR of the Brn-4 mRNA in MSCs. Expression of as-miR-937 significantly increased Brn-4 protein levels in MSCs. Transplantation of as-miR-937-expressing MSCs significantly reduced the deposition of Aβ, increased the levels of BDNF, and significantly improved the appearance in SR and PM-DAT in AD mice.

CONCLUSION

Overexpression of as-miR-937 in MSCs may substantially improve the therapeutic effects of MSCs on AD, possibly through augmenting Brn-4 levels in MSCs.