Amyloid-beta Precursor Protein Induces Glial Differentiation of Neural Progenitor Cells by Activation of the IL-6/gp130 Signaling Pathway
Abbreviated Journal Title
Cytokine; STAT3; JAK1; GFAP; Neural stem cells; Alzheimer's disease; Down syndrome; EMBRYONAL CARCINOMA-CELLS; STEM-CELLS; TRANSDUCER GP130; GENE-EXPRESSION; SECRETED FORMS; GROWTH-FACTOR; JAK2 KINASE; BRAIN; PHOSPHORYLATION; INTERLEUKIN-6; Neurosciences
Although amyloid precursor protein (APP) due to the cytotoxicity of A beta peptides, has been intensively studied, the physiological role of APP still remains wrapped up in veil. In this article, we propose that alpha-cleaved ectodomain of APP (sAPP alpha) 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 sAPP alpha on the IL-6/gp130 signaling pathway. Application of sAPP alpha promoted mRNA expression of gp130, ciliary neurotrophic factor (CNTF), and Janus kinase 1 (JAK1). sAPP alpha 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 sAPP alpha. RNA's interference of CNTF dose-dependently inhibited GFAP expression upregulated by treatment with sAPP alpha. This study suggests that the IL-6/gp130 signaling pathway is involved in sAPP alpha-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.
"Amyloid-beta Precursor Protein Induces Glial Differentiation of Neural Progenitor Cells by Activation of the IL-6/gp130 Signaling Pathway" (2010). Faculty Bibliography 2010s. 397.