N-cadherin enhances APP dimerization at the extracellular domain and modulates Aβ production.

Sequential processing of amyloid precursor protein (APP) by beta- and gamma-secretase leads to the generation of amyloid-beta (A beta) peptides, which plays a central role in Alzheimer's disease pathogenesis. APP is capable of forming a homodimer through its extracellular domain as well as transmembrane GXXXG motifs. A number of reports have shown that dimerization of APP modulates A beta production. On the other hand, we have previously reported that N-cadherin-based synaptic contact is tightly linked to A beta production. In the present report, we investigated the effect of N-cadherin expression on APP dimerization and metabolism. Here, we demonstrate that N-cadherin expression facilitates cis-dimerization of APP. Moreover, N-cadherin expression led to increased production of A beta as well as soluble APP beta, indicating that beta-secretase-mediated cleavage of APP is enhanced. Interestingly, N-cadherin expression affected neither dimerization of C99 nor A beta production from C99, suggesting that the effect of N-cadherin on APP metabolism is mediated through APP extracellular domain. We confirmed that N-cadherin enhances APP dimerization by a novel luciferase-complementation assay, which could be a platform for drug screening on a high-throughput basis. Taken together, our results suggest that modulation of APP dimerization state could be one of mechanisms, which links synaptic contact and A beta production.