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The therapeutic potentials of human neural stem cells transplantation into the brain of the APPsw (amyloid β precursor protein swedish mutation) transgenic mice

Other Titles
 알쯔하이머질환 모델에서 인간 신경줄기세포 뇌 이식이 치료의 유용성 
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Dept. of Medical Science/박사
Alzheimer''s disease (AD) is an inexorable neurodegenerative disease that commonly occurs in elderly adults. AD patients exhibit memory loss and cognitive impairment. The postmortem brains of AD patients reveal abnormal accumulations of amyloid beta (Aβ) in the spaces around synapses and of a hyperphosphorylated form of the tau protein in the cell bodies of neurons. These Aβ peptides and hyperphosphorylated tau cause synaptic dysfunction, generate neuroinflammation, disturb neuronal ionic homeostasis, and advance neuronal injury in AD. Neural stem cells (NSCs) have the capacity for self-renewal and can give rise to differentiated neural cell types; neurons, astrocytes and oligodendrocytes. When NSCs are administrated into a diseased or injured brain, they show not only preferential extensive migration to and engraftment within areas of lesions but also the capability to replace injured cells in an appropriate manner. Apart from replacing lost cells, NSCs based therapy can provide a regenerative environment for other cells residing in diseased brains. In the present study, we investigated the therapeutic potentials of human NSCs by using AD animal model expressing the human APP695 Swedish mutant (KM595/596NL) directed by the NSE promoter (APPsw trasgenic mice) and APPsw-expressing SK-N-MC cells. Human NSCs (hNSCs) were isolated from human fetal telencephalon at 13 weeks of gestation and cultured as neurospheres. When naturally secreted Aβ oligomers derived from APPsw-expressing SK-N-MC cells were directly administered to hNSCs, cells showed the decreased proliferation and enhanced differentiation into glial cells in vitro. After the transplantation of hNSCs into the lateral ventricles (LVs) of 13-month-old APPsw transgenic mice, donor-derived cells showed the engraftment, migration and integration into the host brains. Some of transplanted cells differentiated into neurons, astrocytes and oligodendrocytes, but most of cells remained as immature cells. Human NSCs grafts effectively reduced the level of soluble Aβ42 and phosphorylated tau in the cortex and hippocampus of the mice through the presence of distinct Aβ degradases and neurotrophins produced by implanted cells. Additionally, the administration of hNSCs had a neuroprotective effect via the secretion of trophic factors and anti-inflammatory cytokines, therefore reduced cell death and inflammation in the host brain. Finally, hNSC grafts significantly improved spatial memory and motor learning in the transgenic mice compared to the mice in which H-H buffer was injected into the brain. These findings suggest that human NSCs act through multiple potentially therapeutic actions to benefit AD mice.
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1. College of Medicine (의과대학) > Others (기타) > 3. Dissertation
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