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

The amyloid precursor protein (APPwt) generates amyloid-beta (A{beta}) fragments, which accumulate in plaques characteristic of Alzheimer's disease (AD). A{beta} is believed to arise in neuronal endosomes. Swedish APP (APPSwe) shows elevated A{beta} production and a propensity for early onset AD, yet it remains uncertain whether APPwt and APPSwe diverge in their cellular transport mechanisms.

To address this, researchers utilized live-cell microscopy with cutting-edge imaging techniques in cultured hippocampal neurons to elucidate APP trafficking routes. The findings revealed that APPwt and APPSwe exhibit distinct trafficking patterns. APPSwe is segregated into a supplementary vesicular compartment at the trans-Golgi network.

Furthermore, APPSwe that reaches the dendritic plasma membrane is less prone to be directed towards lysosomes and exhibits a higher tendency to transcytose toward the axon. Crucially, the study also uncovered that amyloidogenic cleavage of APP is not confined to endosomes, but also transpires in vesicles originating from the Golgi apparatus.

These observations suggest that signaling molecules within the APP ectodomain regulate its sorting process, and the heightened A{beta} production observed in APPSwe results from its unique cellular trafficking dynamics.