Altered Nup153 Expression Impairs the Function of Cultured Hippocampal Neural Stem Cells Isolated from a Mouse Model of Alzheimer's Disease
Altered Nup153 Expression Impairs the Function of Cultured Hippocampal Neural Stem Cells Isolated from a Mouse Model of Alzheimer's Disease
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DOI：
10.1007/s12035-018-1466-1
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发表时间：
2019-08-01
影响因子：
5.1
通讯作者：
Grassi, Claudio
中科院分区：
文献类型：
--
作者：
Leone, Lucia;Colussi, Claudia;Grassi, Claudio
成年海马神经发生障碍是阿尔茨海默病(AD)的早期事件，在阿尔茨海默病(AD)相关的认知功能障碍中起关键作用。然而，阿尔茨海默病神经发生缺陷的机制仍不清楚。最近，核孔蛋白Nup153被描述为成体神经干细胞(NSC)维持和命运的一个新的表观遗传学决定因素。在这里，我们研究了Nup153功能障碍是否会影响AD患者NSCs的可塑性。Nup153在AD-NSCs中的表达及其与转录因子Sox2的相互作用显著降低，Sox2是NSC干性及其神经元分化的主要调节因子。在用淀粉样β蛋白(Aβ)或一氧化氮供体刺激的WT-NSCs中，也观察到类似的Nup153减少。因此，无论是用伽马分泌酶抑制剂还是抗氧化剂化合物处理的AD-NSCs都显示出更高的Nup153水平，这表明亚硝化胁迫和Aβ积累都影响Nup153的表达。值得注意的是，通过BrdU掺入、神经球试验和干细胞基因表达分析，AD-NSCs中Nup153水平的恢复促进了它们的增殖。Nup153过表达也恢复了AD-NSC对分化的反应，增加了前神经元基因的表达，神经元标志物阳性细胞的百分比，并获得了更成熟的神经元表型。电生理记录显示，Nup153-AD-NSCs分化的神经元表现出更高的Na+电流密度，与WT-NSCs分化的神经元相似。我们的数据揭示了Nup153在AD动物模型神经干细胞中的一个新的作用，并指出Nup153是恢复神经退行性疾病中NSC生理行为和命运的潜在靶点。
Impairment of adult hippocampal neurogenesis is an early event in Alzheimer's disease (AD), playing a crucial role in cognitive dysfunction associated with this pathology. However, the mechanisms underlying defective neurogenesis in AD are still unclear. Recently, the nucleoporin Nup153 has been described as a new epigenetic determinant of adult neural stem cell (NSC) maintenance and fate. Here we investigated whether Nup153 dysfunction could affect the plasticity of NSCs in AD. Nup153 expression was strongly reduced in AD-NSCs, as well as its interaction with the transcription factor Sox2, a master regulator of NSC stemness and their neuronal differentiation. Similar Nup153 reduction was also observed in WT-NSCs treated with amyloid-beta (A beta) or stimulated with a nitric oxide donor. Accordingly, AD-NSCs treated with either a gamma-secretase inhibitor or antioxidant compounds showed higher Nup153 levels suggesting that both nitrosative stress and A beta accumulation affect Nup153 expression. Of note, restoration of Nup153 levels in AD-NSCs promoted their proliferation, as assessed by BrdU incorporation, neurosphere assay, and stemness gene expression analysis. Nup153 overexpression also recovered AD-NSC response to differentiation, increasing the expression of pro-neuronal genes, the percentage of cells positive for neuronal markers, and the acquisition of a more mature neuronal phenotype. Electrophysiological recordings revealed that neurons differentiated from Nup153-transfected AD-NSCs displayed higher Na+ current density, comparable to those deriving from WT-NSCs. Our data uncover a novel role for Nup153 in NSCs from animal model of AD and point to Nup153 as potential target to restore physiological NSC behavior and fate in neurodegenerative diseases.