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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Modulation of human neural stem cell differentiation in Alzheimer (APP23) transgenic mice by phenserine
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Modulation of human neural stem cell differentiation in Alzheimer (APP23) transgenic mice by phenserine

机译：苯丙氨酸对阿尔茨海默氏症（APP23）转基因小鼠中人类神经干细胞分化的调节

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In a previous study, we found that human neural stem cells (HNSCs) exposed to high concentrations of secreted amyloid-precursor protein (sAPP) in vitro differentiated into mainly astrocytes, suggesting that pathological alterations in APP processing during neurodegenerative conditions such as Alzheimer's disease (AD) may prevent neuronal differentiation of HNSCs. Thus, successful neuroplacement therapy for AD may require regulating APP expression to favorable levels to enhance neuronal differentiation of HNSCs. Phenserine, a recently developed cholinesterase inhibitor (ChEI), has been reported to reduce APP levels in vitro and in vivo. In this study, we found reductions of APP and glial fibrillary acidic protein (GFAP) levels in the hippocampus of APP23 mice after 14 days treatment with (+)-phenserine (25 mg/kg) lacking ChEI activity. No significant change in APP gene expression was detected, suggesting that (+)-phenserine decreases APP levels and reactive astrocytes by posttranscription regulation. HNSCs transplanted into (+)-phenserine-treated APP23 mice followed by an additional 7 days of treatment with (+)-phenserine migrated and differentiated into neurons in the hippocampus and cortex after 6 weeks. Moreover, (+)-phenserine significantly increased neuronal differentiation of implanted HNSCs in hippocampal and cortical regions of APP23 mice and in the CA1 region of control mice. These results indicate that (+)-phenserine reduces APP protein in vivo and increases neuronal differentiation of HNSCs. Combination use of HNSC transplantation and treatment with drugs such as (+)-phenserine that modulate APP levels in the brain may be a useful tool for understanding mechanisms regulating stem cell migration and differentiation during neurodegenerative conditions in AD.
机译：在先前的研究中，我们发现暴露于高浓度分泌淀粉样前体蛋白（sAPP）的人类神经干细胞（HNSCs）在体外主要分化为星形胶质细胞，这表明在神经退行性疾病如阿尔茨海默氏病（ AD）可能会阻止HNSC的神经元分化。因此，成功的AD神经放置疗法可能需要将APP表达调节至有利水平，以增强HNSC的神经元分化。据报道，最近开发的胆碱酯酶抑制剂（ChEI）Phenserine可降低体内和体外的APP水平。在这项研究中，我们发现用缺乏ChEI活性的（+）-酚（25 mg / kg）治疗14天后，APP23小鼠海马中APP和神经胶质纤维酸性蛋白（GFAP）水平降低。没有检测到APP基因表达的显着变化，表明（+）-酚精通过转录后调节降低了APP水平和活性星形胶质细胞。将HNSCs移植到（+）-酚精处理的APP23小鼠中，然后再进行6天的（+）-酚精迁移和分化为海马和皮层神经元的7天治疗。此外，（+）-芬丝氨酸显着增加了APP23小鼠海马区和皮质区以及对照小鼠CA1区中植入的HNSC的神经元分化。这些结果表明，（+）-芬丝氨酸可减少体内APP蛋白并增加HNSC的神经元分化。 HNSC移植与可调节大脑中APP水平的药物（如（+）-非丝氨酸）联合使用可能是了解AD神经退行性疾病期间调节干细胞迁移和分化机制的有用工具。

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