Lai W.-B.Wang B.-J.Hu M.-K.WEN-MING HSUHer G.M.Liao Y.-F.2020-03-052020-03-0520140893-7648https://www.scopus.com/inward/record.uri?eid=2-s2.0-84896549076&doi=10.1007%2fs12035-013-8580-x&partnerID=40&md5=cc249065b8422383e82c488e695964c6https://scholars.lib.ntu.edu.tw/handle/123456789/469993Alzheimer'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. ? 2013 Springer Science+Business Media.[SDGs]SDG3amyloid beta protein; amyloid precursor protein; amyloid precursor protein C99; amyloid precursor protein intracellular domain; dasatinib; ephrin receptor A4; gamma secretase; proteasome; protein kinase Lyn; ubiquitin; unclassified drug; amyloid precursor protein; ephrin receptor A4; ligand; lyn protein-tyrosine kinase; protein tyrosine kinase; article; cell strain HEK293; controlled study; embryo; enzyme activity; human; human cell; implantable cardioverter defibrillator; ligand binding; neuropathology; positive feedback; protein aggregation; protein degradation; protein function; protein homeostasis; protein phosphorylation; receptor upregulation; signal transduction; cell culture; genetics; HEK293 cell line; metabolism; physiology; T lymphocyte; Amyloid beta-Protein Precursor; Cells, Cultured; HEK293 Cells; Humans; Ligands; Proteolysis; Receptor, EphA4; Signal Transduction; src-Family Kinases; T-Lymphocytesjournal article10.1007/s12035-013-8580-x242179502-s2.0-84896549076