Swedish APP follows distinct neuronal trafficking itineraries that underlie its increased β-cleavage

The amyloid precursor protein (APP) cleavage product Aβ comprises amyloid plaques in Alzheimer’s disease (AD). Aβ production is thought to occur in neuronal endosomes. Swedish APP (APP ^Swe ) is associated with increased Aβ production and early onset AD, but it is unclear if APP ^wt and APP ^Swe 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. APP ^wt and APP ^Swe differed in their trafficking. APP ^Swe was sorted into an additional vesicle population at the trans-Golgi. APP ^Swe 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 motifs in the APP ectodomain direct its sorting and that increased Aβ production of APP ^Swe is facilitated by its specific trafficking.