Amyloid-β precursor protein induces glial differentiation of neural progenitor cells by activation of the IL-6/gp130 signaling pathway.
Amyloid-β precursor protein induces glial differentiation of neural progenitor cells by activation of the IL-6/gp130 signaling pathway.
复制标题
淀粉样蛋白-β 前体蛋白通过激活 IL-6/gp130 信号通路诱导神经祖细胞的神经胶质分化。
DOI：
10.1007/s12640-010-9170-6
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发表时间：
2010
影响因子：
3.7
通讯作者：
Sugaya,Kiminobu
中科院分区：
文献类型：
--
作者：
Kwak,Young-Don;Dantuma,Elise;Merchant,Stephanie;Bushnev,Sergey;Sugaya,Kiminobu
淀粉样前体蛋白（amyloid precursor protein，APP）由于Aβ肽的细胞毒性作用而被广泛研究，但APP的生理作用仍被掩盖。在这篇文章中，我们提出α-裂解的APP胞外域（sAPPα）刺激IL-6/gp 130信号通路诱导神经祖细胞（NPC）内的胶质细胞生成。在我们以前的研究中，高剂量APP诱导NPC分化为胶质细胞酸性蛋白（GFAP）阳性细胞。为了阐明APP诱导胶质细胞分化的机制，我们检测了sAPPα对IL-6/gp 130信号通路的影响。应用sAPPα促进gp 130、睫状神经营养因子（CNTF）和Janus激酶1（JAK 1）的mRNA表达。sAPPα通过上调gp 130的表达和磷酸化促进胶质细胞分化。而STAT 3的mRNA表达不变，STAT 3-Tyr 705的磷酸化逐渐增加。应用STAT 3的小干扰RNA（siRNA）抑制GFAP的表达，即使在存在APP的情况下。用JAK 1的siRNA或抑制剂AG 490处理有效地抑制STAT 3磷酸化和GFAP的表达。在sAPPα短期或长期治疗中均观察到CNTF上调。CNTF的RNA干扰可剂量依赖性地抑制sAPPα上调的GFAP表达。本研究提示IL-6/gp 130信号通路参与了sAPPα诱导的NPCs胶质分化。虽然还需要进一步的研究，这项研究可能提供深入了解的神经胶质细胞分化的机制，在阿尔茨海默病或唐氏综合征的病理条件下。
Although amyloid precursor protein (APP) due to the cytotoxicity of Aβ peptides, has been intensively studied, the physiological role of APP still remains wrapped up in veil. In this article, we propose that α-cleaved ectodomain of APP (sAPPα) stimulates the IL-6/gp130 signaling pathway for induction of gliogenesis within neural progenitor cells (NPCs). In our previous study, a high dose of APP differentiated NPCs into glial fibrillary acidic protein (GFAP) positive cells. In order to elucidate the mechanism of APP-induced glial differentiation, we examined the effects of sAPPα on the IL-6/gp130 signaling pathway. Application of sAPPα promoted mRNA expression of gp130, ciliary neurotrophic factor (CNTF), and Janus kinase 1 (JAK1). sAPPα stimulated the glial differentiation by upregulating the expression and phosphorylation of gp130. While mRNA expression of STAT3 was unchanged, phosphorylation of STAT3-Tyr705 gradually increased. Application of small interference RNA (siRNA) for STAT3 suppressed GFAP expression even in the presence of APP. Treatment with siRNA or inhibitor, AG490, of JAK1 efficiently suppressed STAT3 phosphorylation and GFAP expression. Upregulation of CNTF was observed in either short- or long-term treatment with sAPPα. RNA’s interference of CNTF dose-dependently inhibited GFAP expression upregulated by treatment with sAPPα. This study suggests that the IL-6/gp130 signaling pathway is involved in sAPPα-induced glial differentiation of NPCs. Although further investigation is needed, this study may provide insight into the mechanism of glial differentiation of NPCs under pathological conditions in Alzheimer’s disease or Down syndrome.