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
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.