Gain of BDNF Function in Engrafted Neural Stem Cells Promotes the Therapeutic Potential for Alzheimer's Disease.
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 Ca(2+)-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.
Institute of Basic Medical Science, College of Medicine, National Cheng Kung University, Tainan, Taiwan.|Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Cheng-Chun
CC
Wu
Institute of Neuroscience, National Yang-Ming University, Taipei, Taiwan.
Cheng-Chang
CC
Lien
Institute of Neuroscience, National Yang-Ming University, Taipei, Taiwan.
Wen-Hsien
WH
Hou
Institute of Basic Medical Science, College of Medicine, National Cheng Kung University, Tainan, Taiwan.|Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Po-Min
PM
Chiang
Institute of Basic Medical Science, College of Medicine, National Cheng Kung University, Tainan, Taiwan.|Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.|Center of Clinical Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Kuen-Jer
KJ
Tsai
D000544:Alzheimer Disease / Q000628:therapy*; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics* / Q000378:metabolism*; D002454:Cell Differentiation; D002468:Cell Physiological Phenomena; D017690:Cell Transplantation / Q000379:methods*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D015870:Gene Expression; D051379:Mice; D058953:Neural Stem Cells / Q000378:metabolism*; D016896:Treatment Outcome
D019208:Brain-Derived Neurotrophic Factor