Molecular Neurobiology, University of Bielefeld, Bielefeld, Germany.
Department of Cell Biology, University of Bielefeld, Bielefeld, Germany.
Sci Rep. 2018 Oct 30;8(1):16012. doi: 10.1038/s41598-018-34394-8.
Protection of neurons against oxidative stress is crucial during neuronal development, maintenance and for treating neurodegenerative diseases. However, little is known about the molecular mechanisms underlying sex-specific maturation and survival of neurons. In the present study, we demonstrate NF-κB-p65 mediated neuroprotection in human glutamatergic neurons differentiated from inferior turbinate stem cells (ITSCs) in a sex-dependent manner. We successfully differentiated ITSCs into MAP-2/NF200/Synaptophysin/vGlut2-glutamatergic neurons in vitro and ex vivo and validated their functionality. TNF-α-dependent NF-κB-p65 activation was accompanied by significant neuroprotection against oxidative stress-induced neuronal death, which was surprisingly higher in neurons from female donors. Accordingly, sex-specific neuroprotection of female neurons was followed by an increased expression of special NF-κB target genes SOD2 and IGF2. Among these, SOD2 is a well known gene protecting cells against oxidative stress resulting in longevity. In addition, IGF2 is known to promote synapse formation and spine maturation, and it has antioxidant and neuroprotective effects against oxidative damage. In conclusion, we show that NF-κB-p65 is a key player in neuroprotection of human neurons, however the protective gene expression program beneath it differs between sexes. Our findings are in accordance with the increasing evidences pointing towards sex-specific differences in risk and severity of neurodegenerative diseases.
神经元对抗氧化应激的保护在神经元发育、维持和治疗神经退行性疾病中至关重要。然而，关于性别特异性神经元成熟和存活的分子机制知之甚少。在本研究中，我们证明了 NF-κB-p65 在人谷氨酸能神经元中介导神经保护作用，这种作用具有性别依赖性。我们成功地将 ITSC 体外分化为 MAP-2/NF200/Synaptophysin/vGlut2-谷氨酸能神经元，并在体外和体内验证了其功能。TNF-α依赖性 NF-κB-p65 激活伴随着对氧化应激诱导的神经元死亡的显著神经保护作用，而来自女性供体的神经元的神经保护作用更高。因此，女性神经元的性别特异性神经保护作用伴随着特殊 NF-κB 靶基因 SOD2 和 IGF2 的表达增加。其中，SOD2 是一种众所周知的基因，可保护细胞免受氧化应激，从而延长寿命。此外，IGF2 已知可促进突触形成和棘突成熟，具有抗氧化和神经保护作用，可抵抗氧化损伤。总之，我们表明 NF-κB-p65 是人类神经元神经保护的关键因素，但其下的保护基因表达谱在性别之间存在差异。我们的发现与越来越多的证据一致，这些证据表明神经退行性疾病的风险和严重程度存在性别特异性差异。
