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Published online
doi:10.1083/jcb.200809151
The Journal of Cell Biology, Vol. 185, No. 3, 551-564
The Rockefeller University Press, 0021-9525 $30.00
© Inoue et al.
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Article

Synaptic activity prompts {gamma}-secretase–mediated cleavage of EphA4 and dendritic spine formation



Eiji Inoue1, Maki Deguchi-Tawarada1, Aki Togawa1, Chiyuki Matsui1, Kohei Arita1, Sayaka Katahira-Tayama1, Toshitaka Sato2, Emiko Yamauchi2, Yoshiya Oda2, and Yoshimi Takai3

1 KAN Research Institute, Kobe 650-0047, Japan
2 Laboratory of Core Technology, Eisai Co., Ltd., Ibaraki 300-2635, Japan
3 Division of Molecular and Cellular Biology, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan

Correspondence to Eiji Inoue: e-inoue{at}kan.eisai.co.jp

Alzheimer's disease is an age-dependent neurodegenerative disorder that is characterized by a progressive decline in cognitive function. {gamma}-secretase dysfunction is evident in many cases of early onset familial Alzheimer's disease. However, the mechanism by which {gamma}-secretase dysfunction results in memory loss and neurodegeneration is not fully understood. Here, we demonstrate that {gamma}-secretase is localized at synapses and regulates spine formation. We identify EphA4, one of the Ephrin receptor family members, as a substrate of {gamma}-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 {gamma}-secretase affects the pathogenesis of Alzheimer's disease.

Abbreviations used in this paper: AMPA, {alpha}-amino-3-hydroxy-5-methyl-4--isoxazolepropionic acid; CTF, C-terminal fragment; DIV, day in vitro; GluR1, glutamate receptor 1; ICD, intracellular domain; MMP, matrix metalloprotease; NMDA, N-methyl-D-aspartic acid; PS, presenilin.

© 2009 Inoue et al.
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