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

ABSTRACT: Sequential processing of amyloid precursor protein (APP) by ?- and ?-secretase leads to the generation of amyloid-? (A?) 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? production. On the other hand, we have previously reported that N-cadherin-based synaptic contact is tightly linked to A? 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? as well as soluble APP?, indicating that ?-secretase-mediated cleavage of APP is enhanced. Interestingly, N-cadherin expression affected neither dimerization of C99 nor A? 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? production.

SUBMITTER: Asada-Utsugi M 

PROVIDER: S-EPMC3395082 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature