N-cadherin-based adhesion enhances Aβ release and decreases

In neurons, Presenilin 1(PS1)/γ-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/γ-secretase. We postulated that N-cadherin-mediated trafficking of PS1 might impact synaptic PS1-APP interactions and Aβ generation. In the present report, we evaluate the effect of Ncadherin-based contacts on Aβ production. We demonstrate that stable expression of N-cadherin in Chinese Hamster Ovary (CHO) cells, expressing the Swedish mutant of human amyloid precursor protein (APP) leads to enhanced secretion of Aβ in the medium. Moreover, N-cadherin expression decreased Aβ42/40 ratio. The effect of N-cadherin expression on Aβ production was accompanied by the enhanced accessibility of PS1/γ-secretase to APP as well as a conformational change of PS1, as demonstrated by the fluorescence lifetime imaging technique (FLIM). These results indicate that N-cadherin-mediated synaptic adhesion may modulate Aβ secretion as well as the Aβ42/40 ratio via PS1/N-cadherin interactions.