N-cadherin-based adhesion enhances Abeta release and decreases Abeta42/40 ratio.
In neurons, Presenilin 1(PS1)/gamma-secretase is located at the synapses, bound to N-cadherin. We have previously reported that N-cadherin-mediated cell-cell contact promotes cell-surface expression of PS1/gamma-secretase. We postulated that N-cadherin-mediated trafficking of PS1 might impact synaptic PS1-amyloid precursor protein interactions and Abeta generation. In the present report, we evaluate the effect of N-cadherin-based contacts on Abeta production. We demonstrate that stable expression of N-cadherin in Chinese hamster ovary cells, expressing the Swedish mutant of human amyloid precursor protein leads to enhanced secretion of Abeta in the medium. Moreover, N-cadherin expression decreased Abeta(42/40) ratio. The effect of N-cadherin expression on Abeta production was accompanied by the enhanced accessibility of PS1/gamma-secretase to amyloid precursor protein as well as a conformational change of PS1, as demonstrated by the fluorescence lifetime imaging technique. These results indicate that N-cadherin-mediated synaptic adhesion may modulate Abeta secretion as well as the Abeta(42/40) ratio via PS1/N-cadherin interactions.
Uemura
Kengo
K
Department of Neurology, Graduate School of Medicine, Kyoto University, 53 Shogoinkawahara-cho, Sakyo-ku, Kyoto, Japan.
Lill
Christina M
CM
Banks
Mary
M
Asada
Megumi
M
Aoyagi
Nobuhisa
N
Ando
Koichi
K
Kubota
Masakazu
M
Kihara
Takeshi
T
Nishimoto
Takaaki
T
Sugimoto
Hachiro
H
Takahashi
Ryosuke
R
Hyman
Bradley T
BT
Shimohama
Shun
S
Berezovska
Oksana
O
Kinoshita
Ayae
A
D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D015703:Antigens, CD / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D015820:Cadherins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D004622:Embryo, Mammalian; D045604:Extracellular Fluid / Q000187:drug effects / Q000378:metabolism; D015870:Gene Expression / Q000502:physiology; D005786:Gene Expression Regulation / Q000235:genetics; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism*; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism; D051381:Rats; D013329:Structure-Activity Relationship; D014162:Transfection / Q000379:methods; D014255:Trichothecenes / Q000378:metabolism
D016229:Amyloid beta-Peptides; D015703:Antigens, CD; C050361:CDH2 protein, human; D015820:Cadherins; D016895:Culture Media, Serum-Free; D010446:Peptide Fragments; D053764:Presenilin-1; D014255:Trichothecenes; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); C012764:baccharin