Melatonin Prevents Neddylation Dysfunction in Aβ42-Exposed SH-SY5Y Neuroblastoma Cells by Regulating the Amyloid Precursor Protein- Binding Protein 1 Pathway

Author(s): Mayuri Shukla, Vorapin Chinchalongporn, Piyarat Govitrapong*

Journal Name: Current Alzheimer Research

Volume 17 , Issue 5 , 2020

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Abstract:

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.

Keywords: Alzheimer`s, melatonin, amyloid precursor protein-binding protein 1, neddylation, amyloid beta, tau, secretases, β-catenin.

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VOLUME: 17
ISSUE: 5
Year: 2020
Published on: 20 August, 2020
Page: [446 - 459]
Pages: 14
DOI: 10.2174/1567205017666200624201356
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