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

Synaptic activity prompts γ-secretase–mediated cleavage of EphA4 and dendritic spine formation 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. Footnotes Abbreviations used in this paper: AMPA, α-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. Submitted: 22 September 2008 Accepted: 8 April 2009 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png The Journal of Cell Biology Rockefeller University Press

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

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Publisher
Rockefeller University Press
Copyright
© 2009 Inoue et al.
ISSN
0021-9525
eISSN
1540-8140
DOI
10.1083/jcb.200809151
pmid
19414612
Publisher site
See Article on Publisher Site

Abstract

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. Footnotes Abbreviations used in this paper: AMPA, α-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. Submitted: 22 September 2008 Accepted: 8 April 2009

Journal

The Journal of Cell BiologyRockefeller University Press

Published: May 4, 2009

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