Mayuri Shukla, Vorapin Chinchalongporn and Piyarat Govitrapong* Pages 446 - 459 ( 14 )
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.
Alzheimer’s, melatonin, amyloid precursor protein-binding protein 1, neddylation, amyloid beta, tau, secretases, β-catenin.
Chulabhorn Graduate Institute, Chulabhorn Royal Academy, Bangkok 10210, Research Center for Neuroscience, Institute of Molecular Biosciences, Mahidol University, Salaya, Nakhonpathom 73170, Thailand; 3Department of Pharmacology, Faculty of Science, Mahidol University, Bangkok, Chulabhorn Graduate Institute, Chulabhorn Royal Academy, Bangkok 10210