in presenilin 1 (PSEN1) (S169del) or (A246E). We characterized the AD-iPSCs characteristic properties of human pluripotent stem cells and differentiate them into functional neurons. Results: We found abnormally enhanced neuronal differentiation in AD iPSC-derived neural progenitor cells (AD-NPCs), and a reduction in the number of NPCs in AD-NPCs during differentiation. Consistently, we detected a decreased proliferation and an increased apoptosis in differentiating AD-NPCs. In addition, we identified the same phenotypes when PSEN1 with the mutation of A246E was introduced into control iPSCs. Furthermore, knockdown of mutated PSEN1 in AD-NPCs significantly attenuated the premature neuronal differentiation. Our results suggest that PSEN1 mutation causes reduction in the NPC pool, which might be relevant to the neuronal loss in the brain of AD patients. Additionally, our genome-wide transcript analyses identified differentially expressed genes relevant to neuronal differentiation and cell cycle in differentiating AD-NPCs. Conclusion: Collectively, our study uncovers previously unappreciated early NPC dysfunctions in FAD-NPCs and provides new cues to elucidate molecular mechanisms underlying AD development.

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