Background: We found that human neural progenitor cells (HNPCs) exposed to high concentrations of amyloid precursor protein (APP) or transplanted into APP transgenic mice (APP23) primarily differentiated into astrocytes, suggesting that pathological alterations of APP processing in Alzheimer's disease (AD) may prevent neuronal differentiation of HNPCs.
Objectives: To investigate the mechanism of APP-induced glial differentiation of HNPCs.
Methods: We treat HNPCs with APP and analyze the expression and phosphorylation of signaling molecules using PCR and Western blots. To confirm the involvement of the factors, RNA interference of the signaling molecule is conducted.
Results: APP treatment caused inductions of CNTF, gp130 and JAK1 gene expressions, and STAT3 phosphorylation, while silencing of these genes by RNA interference suppressed the glial differentiation of the cells, indicating involvement of the IL-6/gp130 pathway. APP also increased the generation of notch intracellular domain and gene expression of Hes1, indicating that glial differentiation of HNPCs may be mediated by the notch signaling.
Conclusion: These results indicate that APP may regulate HNPC differentiation through activation of both the IL-6/gp130 and notch signaling pathway. Although the importance of adult neurogenesis is not clear, glial differentiation of HNPCs may cause problems in maintaining normal brain function and may contribute to the AD pathology.
2008 S. Karger AG, Basel