English  |  正體中文  |  简体中文  |  Items with full text/Total items : 28611/40649
Visitors : 648067      Online Users : 56
RC Version 4.0 © Powered By DSPACE, MIT. Enhanced by NTU Library IR team.
Scope Adv. Search

Please use this identifier to cite or link to this item: http://ntour.ntou.edu.tw:8080/ir/handle/987654321/43539

Title: Ligand-Dependent Activation of EphA4 Signaling Regulates the Proteolysis of Amyloid Precursor Protein Through a Lyn-Mediated Pathway
Authors: Wei-Bin Lai;Bo-Jeng Wang;Ming-Kuan Hu;Wen-Ming Hsu;Guor Mour Her;Yung-Feng Liao
Contributors: 國立臺灣海洋大學:生命科學系
Keywords: EphA4;Amyloid-β precursor protein;Alzheimer's disease;Amyloid intracellular domain;Amyloid-β;Lyn;Dasatinib γ-Secretase
Date: 2014-04
Issue Date: 2017-09-14T08:42:06Z
Publisher: Molecular Neurobiology
Abstract: Abstract
Alzheimer's disease is the most common dementia afflicting the elderly in modern society. This disease arises from the neurotoxicity elicited by abnormal aggregates of amyloid-β (Aβ) protein. Such aggregates form through the cleavage of amyloid precursor protein (APP) by β-secretase and the subsequent proteolysis of the APP C-terminal fragment (APP-βCTF or C99) by γ-secretase to yield Aβ and APP intracellular domain (AICD). Recent evidence suggests that C99 and AICD may exert harmful effects on cells, suggesting that the proteolytic products of APP, including Aβ, C99, and AICD, could play a pivotal role in neuronal viability. Here, we demonstrate that ligand-activated EphA4 signaling governs the proteostasis of C99, AICD, and Aβ, without significantly affecting γ-secretase activity. EphA4 induced accumulation of C99 and AICD through a Lyn-dependent pathway; activation of this pathway triggered phosphorylation of EphA4, resulting in positive feedback of C99 and AICD proteostasis. Inhibition of EphA4 by dasatinib, a receptor tyrosine kinase inhibitor, effectively suppressed C99 and AICD accumulation. Furthermore, EphA4 signaling controlled C99 and AICD proteolysis through the ubiquitin–proteasome system. In conclusion, we have identified an EphA4–Lyn pathway that is essential for the metabolism of APP and its proteolytic derivatives, thereby providing novel pharmacological targets for the development of anti-Aβ therapeutics for AD.
Relation: 49(2), pp 1055-1068
URI: http://ntour.ntou.edu.tw:8080/ir/handle/987654321/43539
Appears in Collections:[生命科學暨生物科技學系] 期刊論文

Files in This Item:

File Description SizeFormat

All items in NTOUR are protected by copyright, with all rights reserved.


著作權政策宣告: 本網站之內容為國立臺灣海洋大學所收錄之機構典藏,無償提供學術研究與公眾教育等公益性使用,請合理使用本網站之內容,以尊重著作權人之權益。
網站維護: 海大圖資處 圖書系統組
DSpace Software Copyright © 2002-2004  MIT &  Hewlett-Packard  /   Enhanced by   NTU Library IR team Copyright ©   - Feedback