Molecular mechanism of BMSC intracerebral transplantation in impro-ving learning and memory abilities of AD mice / 中国病理生理杂志

ABSTRACT

AIM:To investigate the effect of bone marrow mesenchymal stem cell(BMSC) transplantation on learning and memory abilities and pathological changes of Alzheimer disease (AD) mice and the molecular mechanisms. METHODS:C57/BL6 wild-type (WT) and transgenic(Tg) mice were randomly divided into 4 groupsWT/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 evaluated by Morris water maze test on the 3rd day after surgery. Real-time PCR was applied to detect the mRNA expression of CX3C chemokine ligand 1 (CX3CL1),CX3C chemokine receptor 1 (CX3CR1), IL-1β, TNF-α, Nurr1, YM1, insulin-degrading enzyme (IDE) and matrix metalloproteinase 9(MMP9). The protein levels of CX3CL1 and Aβ42 were measured by ELISA. Western blot was used to detect the protein expression of postsynaptic density protein 95 (PSD95) and synaptophysin (SYP). RE-SULTSThe transplanted BMSCs were observed near the hippocampus of APP/PS1 mice on the 10th 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). Com-pared with Tg/PBS group,the escape latency of Tg/BMSCs group was significantly shorter (P<0.05), and the mRNA 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 mRNA expression of YM1 was up-regulated in WT/BMSCs group and Tg/BMSCs group (P<0.05). Compared with WT/PBS mice, the mRNA expression of TNF-α in the cortex and hippocampus of Tg/PBS group was significantly increased (P<0.05),and the mRNA expression of Nurr1 in the cortex was significantly decreased (P<0.01). Meanwhile,the mRNA expression of TNF-α in the cortex of Tg/BMSCs mice was decreased(P<0.01) and the mRNA 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 group were significantly higher than those in Tg/PBS group (P<0.05). Finally, BMSC transplantation reduced the protein level of Aβ42 in APP/PS1 mice(P<0.05), and increased the mRNA expression of IDE and MMP9 in the hippocampus (P <0.05). CONCLU-SIONBMSC transplantation modulates neuroinflammatory responses and promotes neuroprotective factor and synaptic pro-tein expression,thus improving the learning and memory abilities in the APP/PS1 mice,which may be achieved by up-reg-ulating the expression of CX3CL1.