Melatonin Prevents Neddylation Dysfunction in Aβ42-exposed SH-SY5Y Neuroblastoma Cells by Regulating the Amyloid Precursor ProteinBinding Protein 1 Pathway.

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. METHOD 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 APPBP1 pathway and might preclude the pathogenic mechanisms occurring during disease development, thus providing a propitious therapeutic strategy for preventing AD.