Synaptic activity prompts γ-secretase-mediated cleavage of EphA4 and dendritic spine formation

• Published in: The Journal of cell biology Vol. 185; no. 3; pp. 551 - 564
• Main Authors: Inoue, Eiji, Deguchi-Tawarada, Maki, Togawa, Aki, Matsui, Chiyuki, Arita, Kohei, Katahira-Tayama, Sayaka, Sato, Toshitaka, Yamauchi, Emiko, Oda, Yoshiya, Takai, Yoshimi
• Format: Journal Article
• Language: English
• Published: United States The Rockefeller University Press 04.05.2009; Rockefeller University Press
• Subjects: Alzheimer Disease - pathology; Alzheimer Disease - physiopathology; Alzheimers disease; Amyloid Precursor Protein Secretases - antagonists & inhibitors; Amyloid Precursor Protein Secretases - metabolism; Animals; Antibodies; Dendrites - enzymology; Dendritic spines; Dimethyl Sulfoxide - pharmacology; HEK293 cells; Hippocampus - enzymology; Humans; Lipids; Mice; Neurofibrillary Tangles - pathology; Neurons; Neurons - physiology; NIH 3T3 cells; Physiological regulation; Rafts; Rats; Receptor, EphA4 - metabolism; Receptor, EphA4 - physiology; Spine - cytology; Spine - drug effects; Spine - pathology; Synapses; Synapses - physiology
• ISSN: 0021-9525; 1540-8140
• DOI: 10.1083/jcb.200809151

Alzheimer's disease is an age-dependent neurodegenerative disorder that is characterized by a progressive decline in cognitive function. γ-secretase dysfunction is evident in many cases of early onset familial Alzheimer's disease. However, the mechanism by which γ-secretase dysfunction results in memory loss and neurodegeneration is not fully understood. Here, we demonstrate that γ-secretase is localized at synapses and regulates spine formation. We identify EphA4, one of the Ephrin receptor family members, as a substrate of γ-secretase, and find that EphA4 processing is enhanced by synaptic activity. Moreover, overexpression of EphA4 intracellular domain increases the number of dendritic spines by activating the Rac signaling pathway. These findings reveal a function for EphA4-mediated intracellular signaling in the morphogenesis of dendritic spines and suggest that the processing of EphA4 by γ-secretase affects the pathogenesis of Alzheimer's disease.