Amyloid-β Precursor Protein Induces Glial Differentiation of Neural Progenitor Cells by Activation of the IL-6/gp130 Signaling Pathway

Abstract

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.

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Acknowledgments

We would like to thank Dr. Beth Ostaszewski, Harvard Medical School, and Dr. Thomas Suhduf, University of Texas Southwestern for providing pCEP-APP695, pCMVIg-APP.1 and pCMVIg-APP.2. This study is supported by NIH (R01 AG23472), and Alzheimer’s Association (IIRG-03-5577).

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Correspondence to Kiminobu Sugaya.

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Kwak, YD., Dantuma, E., Merchant, S. et al. Amyloid-β Precursor Protein Induces Glial Differentiation of Neural Progenitor Cells by Activation of the IL-6/gp130 Signaling Pathway. Neurotox Res 18, 328–338 (2010). https://doi.org/10.1007/s12640-010-9170-6

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Keywords

  • Cytokine
  • STAT3
  • JAK1
  • GFAP
  • Neural stem cells
  • Alzheimer’s disease
  • Down syndrome