Department of Neurology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
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. Copyright 2003 Wiley-Liss, Inc.