Synaptic activity prompts gamma-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. 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.
Inoue
Eiji
E
KAN Research Institute, Kobe, Japan. e-inoue@kan.eisai.co.jp
Deguchi-Tawarada
Maki
M
Togawa
Aki
A
Matsui
Chiyuki
C
Arita
Kohei
K
Katahira-Tayama
Sayaka
S
Sato
Toshitaka
T
Yamauchi
Emiko
E
Oda
Yoshiya
Y
Takai
Yoshimi
Y
D000544:Alzheimer Disease / Q000473:pathology / Q000503:physiopathology; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000818:Animals; D003712:Dendrites / Q000201:enzymology*; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D006624:Hippocampus / Q000201:enzymology; D006801:Humans; D051379:Mice; D016874:Neurofibrillary Tangles / Q000473:pathology; D009474:Neurons / Q000502:physiology; D051381:Rats; D036122:Receptor, EphA4 / Q000378:metabolism* / Q000502:physiology*; D013131:Spine / Q000166:cytology / Q000187:drug effects / Q000473:pathology; D013569:Synapses / Q000502:physiology*
D036122:Receptor, EphA4; D053829:Amyloid Precursor Protein Secretases; D004121:Dimethyl Sulfoxide