Title : Nucleoporin 153 deficiency in adult neural stem cells defines a pathological protein-network signature and defective neurogenesis in a mouse model of Alzheimer’s disease
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 at 1 month after LV-Nup153 injection (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 (AD-ORG-Nup) 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.
A proteomic approach was performed to identify Nup153 interactors in WT- and AD-NSCs potentially implicated in neurogenesis regulation. GO analysis showed that Nup153-bound proteins in WT-NSCs were involved in RNA metabolism (tRNA, mRNA, ncRNA, splicing and transport) and epigenetic mechanisms (DNA methylation, histone modifications). Nup153-bound proteins in AD-NSCs were involved in pathways of neurodegeneration and AD, mitochondrial dysfunction, proteasomal processing, cell cycle and RNA degradation. Our data indicate that Nup153 restoration promotes neurogenesis and cognitive performance. Molecular data suggest that the complex regulatory network orchestrated by Nup153 is based on multiple interactions that are differently regulated in WT and AD-NSCs.
What will audience learn from your presentation?
This presentation will provide novel insights in the regulation of adult neurogenesis with a specific focus on:
-novel epigenetic regulators of neural stem cell function
-novel mechanisms of pathogenesis in Alzheimer’s disease
-modeling of development and neurogenesis through brain organoids
-potential therapeutic application to Alzheimer’s disease