NPCs when transplanted to the hippocampus of immune-deficient mice (Supplementary Figure 5). Aβ accumulation has been considered as a late event in AD [42]. Here, we showed that the premature neuronal differentiation began earlier than the changes in Aβ42 and p-tau levels. Consistently, it has been reported that severely impaired proliferation and differentiation of NPCs occurrs preceding the onset of amyloid deposition, neurofibrillary tangles formation and memory impairment in either APPswe/PSEN1ΔE9 or triple transgenic AD mice [43, 44]. Premature neuronal differentiation might gradually reduce NPC pool in the brain long before the emergence of AD clinical symptoms. Accumulating Aβ and p-tau in the brain of AD would further diminish NPC pool and accelerate memory deficit and cognitive decline. Thus, premature neuronal differentiation could be an important and unappreciated early pathogenic event in the pre-clinical stage of AD development, although more systemic investigations are needed.
