Homodimerization of amyloid precursor protein and its implication in the amyloidogenic pathway of Alzheimer's disease

We reported previously that the carbohydrate domain of the amyloid precurso r protein is involved in amyloid precursor protein (APP)-APP interactions. Functional in vitro studies suggested that this interaction occurs through the collagen binding site of APP. The physiological significance remained u nknown, because it is not understood whether and how APP dimerization occur s in vivo. Here we report that cellular APP exists as homodimers matching b est with a two-site model. Consistent with our published crystallographic d ata, we show that a deletion of the entire sequence after the kunitz protea se inhibitor domain did not abolish APP homodimerization, suggesting that t wo domains are criticaIly involved but that neither is essential for homodi merization. Finally, we generated stabilized dimers by expressing mutant AP P with a single cysteine in the ectodomain juxtamembrane region. Mutation o f Lys(624) to cysteine produced similar to6-8-fold more A beta than cells e xpressing normal APP. Our results suggest that amyloid A beta production ca n in principle be positively regulated by dimerization in vivo. We suggest that dimerization could be a physiologically important mechanism for regula ting the proposed signal activity of APP.