Increases of iASPP-Keap1 interaction mediated by syringin enhance synaptic plasticity and rescue cognitive impairments via stabilizing Nrf2 in Alzheimer's models
Increases of iASPP-Keap1 interaction mediated by syringin enhance synaptic plasticity and rescue cognitive impairments via stabilizing Nrf2 in Alzheimer's models
复制标题
在阿尔茨海默病模型中，紫丁香苷介导的 iASPP-Keap1 相互作用增加可增强突触可塑性并通过稳定 Nrf2 来挽救认知障碍
DOI：
10.1016/j.redox.2020.101672
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发表时间：
2020-09-01
期刊：
影响因子：
11.4
通讯作者：
Xu, Ye
中科院分区：
文献类型：
--
作者：
Wang, Chun-Yan;Zhang, Qi;Xu, Ye
氧化应激是阿尔茨海默病（Alzheimer's disease，AD）的一个重要病理表现，它导致突触功能障碍，导致A β蓄积和神经元缠结形成。然而，AD抗氧化防御功能下降的分子机制尚不清楚，有效的AD治疗药物有限。在这里，我们发现，p53的骨化刺激蛋白（iASPP）的抑制剂的减少与淀粉样前体蛋白（APP）/早老素1（PS1）小鼠大脑中氧化应激的脆弱性有关。用抗氧化剂，白藜芦醇苷治疗，可以改善AD相关的病理和行为障碍。有趣的是，白藜芦醇苷处理导致iASPP的上调和iASPP与Kelch样ECH相关蛋白1（Keap 1）相互作用的增加。紫丁香苷减少神经元凋亡独立于p53。我们证实，在体外过表达人瑞典突变APP（APPswe）细胞中，白藜芦醇诱导的抗氧化防御增强涉及Nrf 2的稳定。紫丁香苷介导的Nrf 2核转位通过iASPP/Nrf 2轴促进Nrf 2下游基因的激活。我们的研究结果表明，胡萝卜素介导的iASPP-Keap 1相互作用的增加恢复细胞的氧化还原平衡。进一步研究白藜芦醇苷与iASPP的相互作用有助于理解其调控机制，并设计新型有效的AD治疗调节剂。
Oxidative stress is an important pathogenic manifestation of Alzheimer's disease (AD) that contributes to syn-aptic dysfunction, which precedes A beta accumulation and neurofibrillary tangle formation. However, the molec-ular machineries that govern the decline of antioxidative defence in AD remains to be elucidated, and effective candidate for AD treatment is limited. Here, we showed that the decreases in the inhibitor of apoptosis-stimulating protein of p53 (iASPP) was associated with the vulnerability to oxidative stress in the amyloid precursor protein (APP)/presenilin 1 (PS1) mouse brain. Treatment with an antioxidant, syringin, could ameliorate AD-related pathologic and behavioural impairments. Interestingly, syringin treatment resulted in an upregulation of iASPP and the increase in the interaction of iASPP with Kelchlike ECH-associating protein 1 (Keap1). Syringin reduced neuronal apoptosis independently of p53. We confirmed that syringin-induced enhancement of antioxidant defenses involved the stabilization of Nrf2 in overexpressing human Swedish mutant APP (APPswe) cells in vitro. Syringin-mediated Nrf2 nuclear translocation facilitated the activation of the Nrf2 downstream genes via iASPP/Nrf2 axis. Our results demonstrate that syringin-mediated increases of iASPP-Keap1 interaction restore cellular redox balance. Further study on the syringin-iASPP interactions may help in understanding the regulatory mechanism and designing novel potent modulators for AD treatment.