Reduction of adult hippocampal neurogenesis is an early critical event in Alzheimer’s disease (AD), leading to progressive memory loss and cognitive decline.The nucleoporin Nup153, besides its role in nuclear transport, has been described as a key regulator of NSC plasticity through gene modulation. Here we investigated the potential role of Nup153 as target to improve neurogenesis in the 3xTg mouse model of AD in vitro and in vivo.We found that reduced Nup153 levels characterized NSCs from the 3xTg mice (AD-NSCs) and caused inefficient proliferation, migration and differentiation that were restored by Nup153 overexpression in vitro. Lentiviral-mediated Nup153 hippocampal delivery in AD mice led to an increase in the number of BrdU/DCX+, BrdU/NCAM+ and BrdU/NeuN+ cells at 10 days and 1 month respectively. Consistently, LV-Nup153-injected AD mice showed an improvement of cognitive performance in comparison to AD control mice (MWM test). iPSC-derived brain organoids produced from control and AD patients were also used to further validate the role of Nup153 in neurogenesis and development. AD organoids produced from AD-iPSC transduced with the LV-Nup153 showed a better maturation at 1 month than control-AD-organoids as well as the presence of ventricle-like structures as in healthy control organoids.By proteomics we found that Nup153 binding partners in WT-NSCs were involved in RNA metabolism and epigenetic mechanisms. Nup153-bound proteins in AD-NSCs were involved in pathways of neurodegeneration and AD, mitochondrial dysfunction and proteasomal processing. Our data indicate that Nup153 restoration promotes neurogenesis and cognitive performance and could be used as potential therapeutic target.