Mutations in PSEN1 could bring about alterations in multiple signaling pathways, such as Notch [31], syndecan 3 and N-cadherin [45], which in turn might participate in the development of neurodegeneration in AD. Borghese et. al have clearly demonstrated that inhibition of Notch signaling resulted in a marked acceleration of neuronal differentiation in human ESC-derived NPCs [46], which is consistent with our present finding. Moreover, it is reported that activated HES1 and HES5 expression induced by activation of Notch signaling could inhibit neuronal differentiation in mouse embryos, while HES1 and HES5 mutations would lead to premature neuronal differentiation in embryos [47, 48]. Thus, decreased levels of NICD proteins as well as HES1 and HEY1 transcripts observed in our AD-NPCs could be at least partially responsible for the premature neuronal differentiation. Additionally, β-catenin (CNTTB1) and its cofactor LEF1 were identified as upstream transcription factors of the differentially expressed genes found between AD-NPCs and N-NPCs during differentiation. Hence, disturbed Wnt signaling might be also associated with the premature neuronal differentiation in AD-NPCs. Although iPSCs-based research in the present study provides a new perspective
