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

Journal of Cell Biology, ISSN: 0021-9525, Vol: 185, Issue: 3, Page: 551-564
2009
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Article Description

lzheimer's disease is an age-dependent neuro-degenerative disorder that is characterized by a pro-gressive 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 fnd 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 fndings 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. © 2009 Inoue et al.

Bibliographic Details

Inoue, Eiji; Deguchi-Tawarada, Maki; Togawa, Aki; Matsui, Chiyuki; Arita, Kohei; Katahira-Tayama, Sayaka; Sato, Toshitaka; Yamauchi, Emiko; Oda, Yoshiya; Takai, Yoshimi

Rockefeller University Press

Biochemistry, Genetics and Molecular Biology

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