title: N-cadherin enhances APP dimerization at the extracellular domain and modulates Aβ production.
abstract: Sequential processing of amyloid precursor protein (APP) by β- and γ-secretase leads to the generation of amyloid-β (Aβ) peptides, which plays a central role in Alzheimer's disease pathogenesis. APP is capable of forming a homodimer through its extracellular domain as well as transmembrane GXXXG motifs. A number of reports have shown that dimerization of APP modulates Aβ production. On the other hand, we have previously reported that N-cadherin-based synaptic contact is tightly linked to Aβ production. In the present report, we investigated the effect of N-cadherin expression on APP dimerization and metabolism. Here, we demonstrate that N-cadherin expression facilitates cis-dimerization of APP. Moreover, N-cadherin expression led to increased production of Aβ as well as soluble APPβ, indicating that β-secretase-mediated cleavage of APP is enhanced. Interestingly, N-cadherin expression affected neither dimerization of C99 nor Aβ production from C99, suggesting that the effect of N-cadherin on APP metabolism is mediated through APP extracellular domain. We confirmed that N-cadherin enhances APP dimerization by a novel luciferase-complementation assay, which could be a platform for drug screening on a high-throughput basis. Taken together, our results suggest that modulation of APP dimerization state could be one of mechanisms, which links synaptic contact and Aβ production.
authors.affiliation: School of Health Sciences, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Megumi
authors.initials: M
authors.lastname: Asada-Utsugi
authors.forename: Kengo
authors.initials: K
authors.lastname: Uemura
authors.forename: Yasuha
authors.initials: Y
authors.lastname: Noda
authors.forename: Akira
authors.initials: A
authors.lastname: Kuzuya
authors.forename: Masato
authors.initials: M
authors.lastname: Maesako
authors.forename: Koichi
authors.initials: K
authors.lastname: Ando
authors.forename: Masakazu
authors.initials: M
authors.lastname: Kubota
authors.forename: Kiwamu
authors.initials: K
authors.lastname: Watanabe
authors.forename: Makio
authors.initials: M
authors.lastname: Takahashi
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kihara
authors.forename: Shun
authors.initials: S
authors.lastname: Shimohama
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Takahashi
authors.forename: Oksana
authors.initials: O
authors.lastname: Berezovska
authors.forename: Ayae
authors.initials: A
authors.lastname: Kinoshita
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000096:biosynthesis*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D015153:Blotting, Western; D015820:Cadherins / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects; D019281:Dimerization; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D047468:Immunoprecipitation; D007202:Indicators and Reagents; D010957:Plasmids / Q000235:genetics; D014162:Transfection
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D015820:Cadherins; D007202:Indicators and Reagents; D053829:Amyloid Precursor Protein Secretases