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.
KAN Research Institute, Kobe, Japan. e-inoue@kan.eisai.co.jp
Eiji
E
Inoue
Maki
M
Deguchi-Tawarada
Aki
A
Togawa
Chiyuki
C
Matsui
Kohei
K
Arita
Sayaka
S
Katahira-Tayama
Toshitaka
T
Sato
Emiko
E
Yamauchi
Yoshiya
Y
Oda
Yoshimi
Y
Takai
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