Current Alzheimer Research ( IF 1.8 ) Pub Date : 2020-03-31 , DOI: 10.2174/1567205017666200624201356 Mayuri Shukla 1 , Vorapin Chinchalongporn 2 , Piyarat Govitrapong 1
Background: Amyloid Precursor Protein (APP)-Binding Protein 1 (APP-BP1) is a crucial regulator of many key signaling pathways and functions mainly as a scaffold protein to enhance molecular interactions and facilitate catalytic reactions. The interaction of APP-BP1 with Amyloid Precursor Protein (APP) plays a role in cell cycle transit control, which determines the mechanism behind the loss of cell cycle regulation in Alzheimer’s Disease (AD). In contrast, neddylation, a posttranslational modification mediated by conjugation of ubiquitin-like protein neural precursor cell expressed developmentally downregulated protein 8 (NEDD8), is activated by a heterodimer composed of APP-BP1 and NEDD8-activating enzyme E1 catalytic subunit (Uba3). NEDD8 controls vital biological events, and along with APP-BP1, its levels are deregulated in AD.
Objective: The present study investigated the role of melatonin in regulating the APP-BP1 pathway under both physiological and pathological conditions to develop an understanding of the underlying mechanisms. Methods: Therefore, human SH-SY5Y neuroblastoma cells were treated with various concentrations of Aβ42 to induce neurotoxic conditions comparable to AD. Results: The results are the first to demonstrate that melatonin prevents Aβ42-induced enhancement of APP-BP1 protein expression and alteration in the cellular localization of NEDD8. Moreover, using MLN4924 (APP-BP1 pathway blocker), we also verified the components of the downstream effector cascade of the APP-BP1 pathway, including tau, APP-cleaving secretases, β-catenin and p53. Conclusion: These findings indicate that melatonin regulates the interplay of molecular signaling associated with the APP-BP1 pathway and might preclude the pathogenic mechanisms occurring during disease development, thus providing a propitious therapeutic strategy for preventing AD.中文翻译：
褪黑激素通过调节淀粉样前体蛋白结合蛋白 1 通路来预防 Aβ42 暴露的 SH-SY5Y 神经母细胞瘤细胞的 Neddylation 功能障碍。
背景：淀粉样前体蛋白 (APP) 结合蛋白 1 (APP-BP1) 是许多关键信号通路的关键调节剂，主要作为支架蛋白发挥作用，以增强分子相互作用和促进催化反应。APP-BP1 与淀粉样前体蛋白 (APP) 的相互作用在细胞周期转运控制中发挥作用，这决定了阿尔茨海默病 (AD) 中细胞周期调节丧失背后的机制。相比之下，neddylation 是一种由泛素样蛋白神经前体细胞结合表达发育下调蛋白 8 (NEDD8) 介导的翻译后修饰，由 APP-BP1 和 NEDD8 激活酶 E1 催化亚基 (Uba3) 组成的异源二聚体激活。NEDD8 控制重要的生物事件，并且与 APP-BP1 一起，其水平在 AD 中被解除管制。
目的：本研究调查了褪黑激素在生理和病理条件下调节 APP-BP1 通路的作用，以了解其潜在机制。 方法：因此，用不同浓度的 Aβ42 处理人 SH-SY5Y 神经母细胞瘤细胞以诱导与 AD 相当的神经毒性状况。 结果：该结果首次证明褪黑激素可阻止 Aβ 42诱导的 APP-BP1 蛋白表达增强和 NEDD8 细胞定位的改变。此外，使用 MLN4924（APP-BP1 通路阻断剂），我们还验证了 APP-BP1 通路下游效应子级联的成分，包括 tau、APP 切割分泌酶、β-连环蛋白和 p53。 结论：这些发现表明，褪黑激素调节与 APP-BP1 通路相关的分子信号的相互作用，并可能排除疾病发展过程中发生的致病机制，从而为预防 AD 提供有利的治疗策略。
京公网安备 11010802027423号