Swedish APP follows distinct neuronal traffickingitineraries that underlie its increased Aβ-cleavage

The amyloid precursor protein (APPwt) cleavage product A{beta} comprises amyloid plaques in Alzheimer's disease (AD). A{beta} production is thought to occur in neuronal endosomes. Swedish APP (APPSwe) is associated with increased A{beta} production and early onset AD, but it is unclear if APPwt and APPSwe differ in their neuronal trafficking. We performed quantitative live-cell microscopy with novel imaging-based assays in cultured hippocampal neurons to determine APP trafficking pathways. APPwt and APPSwe differed in their trafficking. APPSwe was sorted into an additional vesicle population at the trans-Golgi. APPSwe that reached the dendritic plasma membrane was less likely to be targeted to lysosomes and more likely to transcytose to the axon. Finally, we determined that amyloidogenic cleavage of APP was not limited to endosomes but also occurred in Golgi-derived vesicles. These results indicate that signals in the APP ectodomain direct its sorting and that increased A{beta} production of APPSwe is facilitated by its specific trafficking.