{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T13:49:16Z","timestamp":1791121756497,"version":"4.1.0"},"reference-count":50,"publisher":"Rockefeller University Press","issue":"3","content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2009,5,4]]},"abstract":"<jats:p>Alzheimer's disease is an age-dependent neurodegenerative disorder that is characterized by a progressive decline in cognitive function. \u03b3-secretase dysfunction is evident in many cases of early onset familial Alzheimer's disease. However, the mechanism by which \u03b3-secretase dysfunction results in memory loss and neurodegeneration is not fully understood. Here, we demonstrate that \u03b3-secretase is localized at synapses and regulates spine formation. We identify EphA4, one of the Ephrin receptor family members, as a substrate of \u03b3-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 \u03b3-secretase affects the pathogenesis of Alzheimer's disease.<\/jats:p>","DOI":"10.1083\/jcb.200809151","type":"journal-article","created":{"date-parts":[[2009,5,4]],"date-time":"2009-05-04T14:12:48Z","timestamp":1241446368000},"page":"551-564","update-policy":"https:\/\/doi.org\/10.1083\/jcb.crossmarkpolicy","source":"Crossref","is-referenced-by-count":100,"title":["Synaptic activity prompts \u03b3-secretase\u2013mediated cleavage of EphA4 and dendritic spine formation"],"prefix":"10.1083","volume":"185","author":[{"given":"Eiji","family":"Inoue","sequence":"first","affiliation":[{"name":"KAN Research Institute, Kobe 650-0047, Japan 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maki","family":"Deguchi-Tawarada","sequence":"additional","affiliation":[{"name":"KAN Research Institute, Kobe 650-0047, Japan 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aki","family":"Togawa","sequence":"additional","affiliation":[{"name":"KAN Research Institute, Kobe 650-0047, Japan 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiyuki","family":"Matsui","sequence":"additional","affiliation":[{"name":"KAN Research Institute, Kobe 650-0047, Japan 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kohei","family":"Arita","sequence":"additional","affiliation":[{"name":"KAN Research Institute, Kobe 650-0047, Japan 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sayaka","family":"Katahira-Tayama","sequence":"additional","affiliation":[{"name":"KAN Research Institute, Kobe 650-0047, Japan 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshitaka","family":"Sato","sequence":"additional","affiliation":[{"name":"Laboratory of Core Technology, Eisai Co., Ltd., Ibaraki 300-2635, Japan 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emiko","family":"Yamauchi","sequence":"additional","affiliation":[{"name":"Laboratory of Core Technology, Eisai Co., Ltd., Ibaraki 300-2635, Japan 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshiya","family":"Oda","sequence":"additional","affiliation":[{"name":"Laboratory of Core Technology, Eisai Co., Ltd., Ibaraki 300-2635, Japan 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshimi","family":"Takai","sequence":"additional","affiliation":[{"name":"Division of Molecular and Cellular Biology, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan 3"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2009,5,4]]},"reference":[{"key":"2023072912284801200_bib2","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1083\/jcb.147.2.277","article-title":"Presenilin 1 controls \u03b3-secretase processing of the amyloid precursor protein in pre-Golgi compartments of hippocampal neurons","volume":"147","author":"Annaert","year":"1999","journal-title":"J. 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