Interleukin-4 restores neurogenic plasticity of the primary human neural stem cells through suppression of Kynurenic acid production upon Amyloid-beta42 toxicity
Interleukin-4 restores neurogenic plasticity of the primary human neural stem cells through suppression of Kynurenic acid production upon Amyloid-beta42 toxicity
复制标题
Interleukin-4 通过抑制淀粉样蛋白 β42 毒性后犬尿酸的产生来恢复原代人类神经干细胞的神经源可塑性
DOI：
10.1101/227306
复制
发表时间：
--
期刊：
影响因子：
--
通讯作者：
Caghan Kizil
中科院分区：
文献类型：
--
作者：
Christos Papadimitriou;Hilal Celikkaya;Mehmet Ilyas I Cosacak;Violeta Mashkaryan;Prabesh Bhattarai;Weilin Lin;Alvin Thomas;Yixin Zhang;Uwe Freudenberg;Carsten Werner;Caghan Kizil
阿尔茨海默病（AD）患者神经干细胞（NSCs）对淀粉样蛋白β 42（Aβ42）毒性的可塑性和神经发生能力的重要决定因素是免疫应答。然而，个别免疫调节效应对神经干细胞可塑性的直接影响仍有待阐明，这也是简化组织模拟培养实验的动机。使用starPEG-肝素水凝胶系统，该系统提供确定的3D细胞指导性神经微环境培养系统，维持人NSC的高水平增殖和神经原性活性，并重现Aβ42给药后淀粉样蛋白毒性的基本病理学后果，我们发现，抗炎细胞因子白细胞介素-4（IL-4）通过抑制Aβ42-诱导犬尿氨酸产生酶犬尿氨酸氨基转移酶2（KAT 2），我们还发现其在AD模型APP/PS1 dE 9小鼠的脑中上调。我们的转录组分析表明，IL 4治疗恢复了NSC和皮质亚型标志物的表达水平。因此，我们的解剖神经微环境培养揭示了IL 4介导的神经炎性串扰对人类NSC可塑性的影响，并预测了AD治疗干预的新机制靶点。
The immune response is an important determinant of the plasticity and neurogenic capacity of neural stem cells (NSCs) upon amyloid-beta42 (Aβ42) toxicity in Alzheimer’s disease (AD). However, the direct effects of individual immuno-modulatory effectors on NSC plasticity remain to be elucidated and are the motivation for reductionist tissue-mimetic culture experiments. Using starPEG-Heparin hydrogel system that provides a defined 3D cell-instructive neuro-microenvironment culture system, sustains high levels of proliferative and neurogenic activity of human NSCs, and recapitulates the fundamental pathological consequences of Amyloid toxicity upon Aβ42 administration, we found that the anti-inflammatory cytokine interleukin-4 (IL4) restores the plasticity and neurogenic capacity of NSCs by suppressing the Aβ42-induced kynurenic acid-producing enzyme kynurenine aminotransferase 2 (KAT2), which we also found to be upregulated in the brains of the AD model, APP/PS1dE9 mouse. Our transcriptome analyses showed that IL4 treatment restores the expression levels of NSC and cortical subtype markers. Thus, our dissective neuro-microenvironment culture revealed IL4-mediated neuroinflammatory crosstalk for human NSC plasticity and predicted a new mechanistic target for therapeutic intervention in AD.
登录
查看更多内容
影响因子：
7.7
作者：
Qiu, Jing;McQueen, Jamie;Hardingham, Giles E.
通讯作者：
Hardingham, Giles E.
DOI：
10.4137/ijtr.s12626
发表时间：
2013-09-15
期刊：
International journal of tryptophan research : IJTR
影响因子：
--
作者：
Jones SP;Guillemin GJ;Brew BJ
通讯作者：
Brew BJ
影响因子：
1.2
作者：
Bhattarai, Prabesh;Thomas, Alvin Kuriakose;Kizil, Caghan
通讯作者：
Kizil, Caghan
影响因子：
56.9
作者：
Kyritsis, Nikos;Kizil, Caghan;Brand, Michael
通讯作者：
Brand, Michael
影响因子：
16.6
作者：
Maitz, Manfred F.;Freudenberg, Uwe;Tsurkan, Mikhail V.;Fischer, Marion;Beyrich, Theresa;Werner, Carsten
通讯作者：
Werner, Carsten