2016 Volumes 01
Xiu-Juan Dong#, Zhi-Wei Chen#, Xu-yin Yang, Long-Wang Zhang, Rui-Shen Xie, Jian Liu1, Feng-Mei Yuan1, Long Hui Zhou*, Zhen-Wu Sun1*
Ibrain 2016;2(1):9-17 Download
Background: Reduction of neurotrophic support in the aging brain is one of the possible mechanisms leading to the development of Alzheimer’s disease (AD). Until now no disease-modifying therapy is available for AD. It is imperative to develop effective therapy for AD. The following paper presented results showing that the transplant of NT-4 gene modified fibroblasts improved cognitive functions in AD rats, likely through the upregulation of BDNF. Methods: Hippocampal umbrella was bilaterally transected to produce a AD model involving chlinergic neuronal degeneration in the basal forebrain of rats. The NT-4 cDNA fragment, cloned from human NT-4 mRNA, was inserted into pcDNA3, then transformed into fibroblats derived from a green fluorescence protein (GFP) transgenic mouse. Then NT-4 gene-modified fibroblasts were transplanted into AD rats, and the behavior was tested by Morris water maze 1 months after cell transplantation. Results: Transplantation of NT-4 gene modified fibroblasts improved cognitive functions and protected cholinergic neurons from the loss of acetylcholine esterase immunoreactivity and upregulated BDNF gene expression. The protective effect of the transplantation on cholinergic neurons was lost in BDNF-knock-down mice. Conclusions: Our results have provided evidence that transplantation of NT-4 gene modified fibroblasts may protect transected cholinergic neurons and improve the cognitive functions in AD via upregulation of BDNF expression.
Zhuo Zhang1,2, Yan Yan2, Bin Sun2, Jia Liu3, Yu-Hong Zhu2*
Ibrain 2016;2(1):1-8 Download
Background: Effective therapy for the treatment of Alzheimer’s disease is far from satisfaction. Bone marrow stromal cells (BMSC) and neurotrophin-4 (NT-4), well known for the protection of cholinergic neuronal survival, are crucial for the treatment of AD, respectively. Combination treatment may be an attractive method for neural repair in AD patients. This study therefore investigated the effects of NT-4 gene modified bone marrow stromal cells on the cognitive ability and memory of AD rats, and explored the protective mechanism. Methods: Human NT-4 RNA was obtained and subjected to reverse transcriptase polymerase chain reaction, followed by recombinant reconstruction. Then, NT-4 gene was transferred into BMSC derived from a green fluorescence protein transgenic mouse. BMSC and NT-4 gene modified BMSC were separately transplanted into the hippocampus of AD rats. Three months after cell transplantation, behaviors and electro-physiology of the rats were assessed. The fate of BMSC in vivo and neuroprotective effect of NT-4 gene modified BMSC for hippocampus neurons was determined, also. Results: NT-4 gene modified BMSC could express high level of NT-4 and showed positive biological activity in vitro. After transplantation, the cognitive ability and electrophysiological elements like p50 of AD rats in the NT-4 gene modified BMSC group exhibited better improvement than in the BMSC group. Transplanted BMSC could survive and migrate in host hippocampus till three months, and increase the ratio number of CHAT positive neurons. Conclusions: Engrafted BMSC expressing NT-4 can survive, migrate and increase ChAT immunopositive neurons for the last function improvement in AD rats. BMSC carrying NT-4 could be as an effective strategy for AD treatment in future clinic trial.
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