Ligand-dependent activation of EphA4 signaling regulates the proteolysis of amyloid precursor protein through a Lyn-mediated pathway.
Mol Neurobiol
; 49(2): 1055-68, 2014 Apr.
Article
in En
| MEDLINE
| ID: mdl-24217950
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-ß (Aß) protein. Such aggregates form through the cleavage of amyloid precursor protein (APP) by ß-secretase and the subsequent proteolysis of the APP C-terminal fragment (APP-ßCTF or C99) by γ-secretase to yield Aß 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 Aß, 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 Aß, 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-Aß therapeutics for AD.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Signal Transduction
/
Amyloid beta-Protein Precursor
/
Src-Family Kinases
/
Receptor, EphA4
/
Proteolysis
Limits:
Humans
Language:
En
Journal:
Mol Neurobiol
Journal subject:
BIOLOGIA MOLECULAR
/
NEUROLOGIA
Year:
2014
Document type:
Article
Affiliation country:
Taiwan