Gain of BDNF Function in Engrafted Neural Stem Cells Promotes the Therapeutic Potential for Alzheimer's Disease.
Gain of BDNF Function in Engrafted Neural Stem Cells Promotes the Therapeutic Potential for Alzheimer's Disease.
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DOI：
10.1038/srep27358
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发表时间：
2016-06-06
影响因子：
4.6
通讯作者：
Tsai KJ
中科院分区：
文献类型：
--
作者：
Wu CC;Lien CC;Hou WH;Chiang PM;Tsai KJ
基于干细胞的治疗是神经退行性疾病的潜在治疗方法，但其在阿尔茨海默病（AD）中的应用仍然有限。脑源性神经营养因子（BDNF）在AD的发病机制和治疗中起关键作用。在这里，我们提出了一种新的治疗AD的治疗方法，使用BDNF过表达的神经干细胞（BDNF-NSCs）。在体外，BDNF过表达对β-淀粉样蛋白处理的NSC具有神经保护作用。在体内，移植的BDNF-NSCs源性神经元不仅表现出Ca 2+反应的波动，表现出成熟神经元的电生理特性，并整合到局部脑回路中，而且恢复了认知功能缺陷。此外，BDNF过表达提高了移植细胞的存活率、神经元的命运、神经突的复杂性、电特性的成熟和突触密度。相反，BDNF-NSC中BDNF的敲低降低了基于干细胞的治疗功效。总之，我们的研究结果表明BDNF过表达通过神经源性效应和神经元替代提高了移植的NSCs对AD的治疗潜力，并进一步支持了基于NSCs的AD离体基因治疗的可行性。
Stem cell-based therapy is a potential treatment for neurodegenerative diseases, but its application to Alzheimer’s disease (AD) remains limited. Brain-derived neurotrophic factor (BDNF) is critical in the pathogenesis and treatment of AD. Here, we present a novel therapeutic approach for AD treatment using BDNF-overexpressing neural stem cells (BDNF-NSCs). In vitro, BDNF overexpression was neuroprotective to beta-amyloid-treated NSCs. In vivo, engrafted BDNF-NSCs-derived neurons not only displayed the Ca2+-response fluctuations, exhibited electrophysiological properties of mature neurons and integrated into local brain circuits, but recovered the cognitive deficits. Furthermore, BDNF overexpression improved the engrafted cells’ viability, neuronal fate, neurite complexity, maturation of electrical property and the synaptic density. In contrast, knockdown of the BDNF in BDNF-NSCs diminished stem cell-based therapeutic efficacy. Together, our findings indicate BDNF overexpression improves the therapeutic potential of engrafted NSCs for AD via neurogenic effects and neuronal replacement, and further support the feasibility of NSC-based ex vivo gene therapy for AD.