基于GSK-3β途径探索人参及其有效成分促进神经干细胞增殖和分化治疗老年痴呆症的机制

Alzheimer's disease (AD) is one of major diseases that impact on health. Neuronal injury and unable to repair itself is a major cause that lead to alzheimer's disease. The ginseng, one of traditional Chinese medicine (TCM), achieved positive effect on alzheimer's disease by the guide of TCM theory “An Shen”, however, the mechanism is currently unknown. Based on the pharmacological research of ginseng and our preliminary findings, we hypothesize that the mechanism of ginseng and its active ingredients in the treatment of AD may be related to the activation of Wnt/β-catenin pathway to promote the proliferation and differentiation of neural stem cells in the brain to replace the damaged neurons. The inhibition of GSK-3β activity may be the target of ginseng and its active ingredients promote the proliferation and differentiation of neural stem cells. In this study, we used RNA interference, lentivirus, confocal, histopathological staining, Western-Blot, qPCR and other techniques, as well as the patented technology of rat autologous neural stem cell extraction. We want to determine the effect of ginseng and its active ingredients on the proliferation and differentiation of neural stem cells in the brain for the treatment of AD animals by overexpress the expression of GSK-3β in autologous neural stem cell, provided a new method for future in vivo brain nerve research. Our study is helpful to decipher the mechanism of ginseng and its active ingredients promoting proliferation and differentiation of neural stem cells by inhibiting the activation of GSK-3β pathway to treat AD, clear the inherent mechanism of the ginseng theory “An Shen” and provide scientific evidences for its clinical application.

老年痴呆症（AD）是影响健康的重大疾病， 神经元的损伤是导致AD的主要原因。人参以“安神”为指导进行AD治疗取得良好的疗效，但其内在机制尚不十分明确。依据既往的研究成果及本课题组的前期研究，我们提出：人参及其有效成分治疗AD的机制可能与激活Wnt/β-catenin途径促进脑部神经干细胞增殖和分化进而取代受损的神经元有关，抑制GSK-3β活性可能是其促进神经干细胞增殖和分化的靶点。本研究拟采用RNA干扰、慢病毒、共聚焦、组织病理学染色、Western-Blot、qPCR等技术，并运用大鼠自体神经干细胞提取的技术，过表达其自体神经干细胞的GSK-3β途径观察人参及其有效成分治疗AD的效果，同时提供一种新的脑部神经研究的体内实验方法。本项目将明确人参及其有效成分抑制GSK-3β途径促进神经干细胞增殖和分化在治疗AD中的作用，丰富人参“安神”的药物机理，为其临床应用提供科学依据。

阿尔兹海默症（AD）是老年痴呆的最常见类型，目前缺乏有效治疗药物。近年研究表明，海马区神经元损伤是导致AD的主要原因，而促进神经干细胞增殖与分化产生新生神经元是治疗AD的有效途径。传统中药人参以“安神”为指导有效治疗AD，但是其内在机制尚不十分明确。本项目根据人参前沿研究进展及我们前期研究基础提出假说：人参有效成分抗AD的机制可能与激活Wnt/GSK-3β/β-catenin途径促进脑部神经干细胞的增殖和分化进而取代受损的神经元有关。本项目通过三年的研究，已经按照计划完成研究内容，研究结果表明人参有效成分（20S-原人参二醇、齐墩果酸及人参总皂苷）可以促进神经干细胞体外增殖与分化产生新生神经元，并通过分子对接、腺病毒基因编辑等技术明确其作用机制是通过抑制GSK-3β蛋白活性激活Wnt/GSK-3β/β-catenin通路。在AD动物模型中，人参有效成分通过激活海马组织Wnt/GSK-3β/β-catenin通路促进海马神经干细胞的增殖与分化产生新生神经元，进而有效改善AD动物的认知损伤状态。本项目的实施为开发以人参有效成分作为抗AD药物提供数据参考，也为以GSK-3β蛋白为药物靶点的新型抗AD药物研发提供科学基础，并为阐释人参“安神”作用提供理论支持。