Uemura Kengo, Kitagawa Naoyuki, Kohno Ryuichi, Kuzuya Akira, Kageyama Takashi, Chonabayashi Kazuhisa, Shibasaki Hiroshi, Shimohama Shun
Department of Neurology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
J Neurosci Res. 2003 Oct 15;74(2):184-91. doi: 10.1002/jnr.10753.
One pathological characteristic of Alzheimer's disease (AD) is extensive synapse loss. Presenilin 1 (PS1) is linked to the pathogenesis of early onset familial Alzheimer's disease (FAD) and is localized at the synapse, where it binds N-cadherin and modulates its adhesive activity. To elucidate the role of the PS1/N-cadherin interaction in synaptic contact, we established SH-SY5Y cells stably expressing wild-type (wt) PS1 and dominant-negative (D385A) PS1. We show that the formation of cadherin-based cell-cell contact among SH-SY5Y cells stably expressing D385A PS1 was suppressed. Conversely, wt PS1 cells exhibited enhanced cell-cell contact and colony formation. Suppression of cell-cell contact in D385A cells was accompanied by an alteration in N-cadherin subcellular localization; N-cadherin was retained mainly in the endoplasmic reticulum (ER) and cell surface expression was reduced. We conclude that PS1 is essential for efficient trafficking of N-cadherin from the ER to the plasma membrane. PS1-mediated delivery of N-cadherin to the plasma membrane is important for N-cadherin to exert its physiological function, and it may control the state of cell-cell contact.
阿尔茨海默病（AD）的一个病理特征是广泛的突触丧失。早老素1（PS1）与早发性家族性阿尔茨海默病（FAD）的发病机制有关，且定位于突触，在突触处它与N-钙黏蛋白结合并调节其黏附活性。为了阐明PS1/N-钙黏蛋白相互作用在突触接触中的作用，我们建立了稳定表达野生型（wt）PS1和显性负性（D385A）PS1的SH-SY5Y细胞系。我们发现，稳定表达D385A PS1的SH-SY5Y细胞之间基于钙黏蛋白的细胞间接触形成受到抑制。相反，wt PS1细胞表现出增强的细胞间接触和集落形成。D385A细胞中细胞间接触的抑制伴随着N-钙黏蛋白亚细胞定位的改变；N-钙黏蛋白主要保留在内质网（ER）中，细胞表面表达减少。我们得出结论，PS1对于N-钙黏蛋白从内质网到质膜的有效转运至关重要。PS1介导的N-钙黏蛋白向质膜的转运对于N-钙黏蛋白发挥其生理功能很重要，并且它可能控制细胞间接触的状态。
