Transplantation Of NGF Genetically Modified Bone Marrow Stromal Stem Cells(BMSC) Into A Rat Model Of Alzheimer' Disease(AD)

Objective:To investigate the effect of engrafted nerve growth factor(NGF)gene genetically modified bone marrow stromal stem cells(BMSC)into AD rat models on survival,migration and differentiation of engrafted cells,pathohistology and behavior of host,provide scientific theoretical and practical foundation to the gene therapy of AD.Methods:Stereo-orientation technique was used to microinject bilaterally theβ-amyloid protein into the hipocampus of rats to reproduce the AD rat models.8-10 days after the AD rat models were made,AD rats were divided into 5 groups,each group had 7 rats:1.normal group which were without any treatment;2.NS group which were subjected to be injected with normal sodium;3.experiment group,AD rat models without transplanted injection;4.AD+BMSC group which were transplanted bilaterally with bone marrow stromal stem cells derived from GFP transgenic mice to the hippocampus;5.NGF-MSC group in which bone marrow stromal stem cells derived from green fluorecent protein(GFP)transgenic mice genetically modified to secrete NGF were transplanted into the hipocampus of AD rat models.2 weeks post of transplantation,the behavior change in AD rats after transplantation was evaluated by Morris water maze.Immunohistochemistry combined with fluorescence microsope was used to examine the survival,migration and differentiation of engrafted BMSC in hippocampus of AD rats.Histological staining was used to test the histological change in host hippocampus after transplantation.Results:The implanted BMSC survived,migrated and expressed NGF as well as differentiated into choline acetyltransferase(ChAT)-positive neurons.Transplanted NGF-MSC could migrate for a distance in host hippocampus.Most transplanted NGF-MSC migrated to the pyramidal cell layer which located at interface between cortex and hippocampus.In BMSC transplanted group,AD rats showed significant improvements in learning and memory than AD model-group(control)(P＜0.05).The NGF gene modified BMSC showed more significant improvements than the BMSC group in learning and memory in AD rats(P＜0.01).The numbers of hippocampal neurons in host was increased significantly when compared with model experiment group,which approached to normal level.Conclusion:Engrafted BMSC and BMSC-NGF into the hipocampus of AD rat models not only could survive,migrate and differentiate into ChAT-positive neurons, but also could significantly improve the behavior in learning and memory and increase the numbers of hippocampal neurons of AD rats,especially in BMSC-NGF transplanted group.BMSC therefore provided an effective carrier for delivery of NGF into AD rats.Administration of NGF gene modified BMSC may be considered as a potential strategy for the development of effective and potential therapies for AD.