Effects Of BMSCs Intracerebral Transplantation On Improving Learning And Memory In AD Mice And Its Mechanism

Aim: To investigate the effect of bone marrow mesenchymal stem cells(BMSCs)transplantation on learning and memory abilities and pathological changes of Alzheimer disease(AD)mice and the molecular mechanisms.Methods: First,primary BMSCs were cultured with purified,and subjected to Osteocyte differentiation and adipogenesis differentiation,Flow cytometry was used to identify BMSCs;APP/PS1 transgenic mice genotypes identified.C57 /BL6 wild-type(WT)and transgenic(Tg)mice were randomly divided into four groups: WT/PBS group,WT/BMSCs group,Tg /PBS group,and Tg /BMSCs group.The mice were administered with PBS or BMSCs via intracere-broventricular injection.Spatial learning and memory abilities of the mice were detected by Morris water maze test on the 3rd day after surgery.Real-time PCR was applied to detect the m RNA expression of CX3 C chemokine ligand 1(CX3CL1),CX3 C chemokine receptor 1(CX3CR1),IL-1?,TNF-?,Nurr1,YM1,insulin-degrading enzyme(IDE)and matrix metalloproteinase 9(MMP9).The protein levels of CX3CL1 and A?42 were measured by ELISA.Western blot was used to detect the protein expression of postsynaptic density protein 95(PSD95)and synaptophysin(SYP).Results: BMSCs have good capabilities of differentiate well into bone and grease,the surface markers of BMSCs CD29,CD105,Sca1 it's highly expressed,and low expression of CD34.APP and PS1 gene expression were detected in transgenic mouse tissues.The transplanted BMSCs were observed near the hippocampus of APP /PS1 mice on the 10 th postoperative day.The escape latency of the mice in Tg /PBS group was significantly longer than that in the WT /PBS mice(P < 0.05).Compared with Tg /PBS group,the escape latency of Tg /BMSCs group was significantly shorter(P < 0.05),and the m RNA and protein levels of CX3CL1 in Tg /BMSCs group were significantly higher than those in Tg /PBS group(P < 0.01).The results of immunohistofluorescence staining showed that BMSC transplantation promoted the activation of microglia in the brain of WT and Tg mice.The m RNA expression of YM1 was up-regulated in WT /BMSCs group and Tg /BMSCs group(P < 0.05).Compared with WT /PBS mice,the m RNA expression of TNF-? in the cortex and hippocampus of Tg /PBS group was significantly increased(P < 0.05),and the m RNA expression of Nurr1 in the cortex was significantly decreased(P < 0.01).Meanwhile,TNF-? m RNA expression of the cortex of Tg /BMSCs mice was decreased(P < 0.01)and the m RNA expression of CX3CR1 and Nurr1 was up-regulated compared with Tg /PBS group(P < 0.05).The results of Western blot showed that the protein levels of PSD95,p85,p110 and p-Akt in Tg /BMSCs were significantly higher than Tg /PBS(P < 0.05).Finally,BMSC transplantation reduced the protein level of A?42 in APP /PS1 mice(P < 0.05),and increased the m RNA expression of IDE and MMP9 in the hippocampus(P < 0.05).Conclusion: Transplantation of BMSCs can reduce the secretion of neuroinflammatory cytokines,promote the expression of neuroprotective and synaptic proteins and improve the learning and memory abilities of APP / PS1 mice.It may be that BMSCs transplantation activates PI3 K / Akt pathway after up-regulating chemokine CX3CL1.