期刊
CURRENT ALZHEIMER RESEARCH
卷 17, 期 5, 页码 446-459出版社
BENTHAM SCIENCE PUBL LTD
DOI: 10.2174/1567205017666200624201356
关键词
Alzheimer's; melatonin; amyloid precursor protein-binding protein 1; neddylation; amyloid beta; tau; secretases; beta-catenin
资金
- Royal Golden Jubilee Ph.D. Program [PHD/0036/2554]
- 60th Year Supreme Reign of his Majesty King Bhumibol Adulyadej Scholarship - Faculty of Graduate Studies Academic Year 2010, Mahidol University
- Thailand Research Fund (TRF) [DPG5780001]
- Chulabhorn Graduate Institute, Chulabhorn Royal Academy
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 A beta(42) to induce neurotoxic conditions comparable to AD. Results: The results are the first to demonstrate that melatonin prevents A beta(42)-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, beta-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.
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