Uemura Kengo, Lill Christina M, Banks Mary, Asada Megumi, Aoyagi Nobuhisa, Ando Koichi, Kubota Masakazu, Kihara Takeshi, Nishimoto Takaaki, Sugimoto Hachiro, Takahashi Ryosuke, Hyman Bradley T, Shimohama Shun, Berezovska Oksana, Kinoshita Ayae
Department of Neurology, Graduate School of Medicine, Kyoto University, 53 Shogoinkawahara-cho, Sakyo-ku, Kyoto, Japan.
J Neurochem. 2009 Jan;108(2):350-60. doi: 10.1111/j.1471-4159.2008.05760.x. Epub 2008 Nov 25.
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.
在神经元中，早老素1（PS1）/γ-分泌酶定位于突触，与N-钙黏着蛋白结合。我们之前曾报道，N-钙黏着蛋白介导的细胞间接触可促进PS1/γ-分泌酶在细胞表面的表达。我们推测，N-钙黏着蛋白介导的PS1转运可能会影响突触处PS1与淀粉样前体蛋白的相互作用以及Aβ的生成。在本报告中，我们评估了基于N-钙黏着蛋白的细胞接触对Aβ产生的影响。我们证明，在中国仓鼠卵巢细胞中稳定表达N-钙黏着蛋白，同时表达人淀粉样前体蛋白的瑞典突变体，会导致培养基中Aβ分泌增加。此外，N-钙黏着蛋白的表达降低了Aβ（42/40）比率。如荧光寿命成像技术所示，N-钙黏着蛋白表达对Aβ产生的影响伴随着PS1/γ-分泌酶与淀粉样前体蛋白的可及性增强以及PS1的构象变化。这些结果表明，N-钙黏着蛋白介导的突触黏附可能通过PS1/N-钙黏着蛋白相互作用调节Aβ分泌以及Aβ（42/40）比率。
