Snapin-mediated BACE1 retrograde transport is essential for its degradation in lysosomes and regulation of APP processing in neurons.

β site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1) is the major β secretase for generating β-amyloid (Aβ) peptides. The acidic environment of endosomes is optimal for β secretase activity. However, the mechanisms regulating BACE1 traffic from endosomes to lysosomes for degradation are largely unknown. Here, using snapin-deficient mice combined with gene rescue experiments, we reveal that Snapin, as a dynein motor adaptor for late endosomes, mediates BACE1 retrograde transport. hAPP mutant live neurons and mouse brains exhibited BACE1 accumulation within the altered late endocytic organelles and defective lysosomal targeting due to reduced Snapin-dynein coupling. Deleting snapin or disrupting Snapin-dynein coupling reduces BACE1 transport to lysosomes for degradation, thus enhancing APP processing. Overexpressing Snapin in hAPP neurons reduces β site cleavage of APP by enhancing BACE1 turnover. Altogether, our study provides mechanistic insights into the complex regulation of BACE1 level and activity and turnover through retrograde transport, thus controlling Aβ generation in neurons.