Overexpression of SNX7 reduces Aβ production by enhancing lysosomal degradation of APP

Highlights: • SNX7 has been proposed to be linked with Alzheimer's disease. • Overexpression of SNX7 reduces the production of Aβ and sAPPβ. • It also reduces the cellular level of APP. • The reduction of APP is reversed by inhibitors of lysosomal degradation. • Our results suggest that SNX7 takes part in directing APP for degradation. Abnormal production of amyloid-β peptides (Aβ) by proteolytic processing of amyloid precursor protein (APP) is thought to be central to the pathogenesis of Alzheimer's disease (AD). Although many efforts have been made to investigate mechanisms that regulate APP processing, many details remain incompletely understood. Sorting nexins (SNXs) are a family of proteins which are involved in many intracellular trafficking events. Several SNXs have been implicated in APP processing and Aβ production. In this study, we extended the investigation to SNX7. We found that overexpression of SNX7 in HEK293T cells reduces the levels of secreted Aβ and β-cleaved N-terminal APP fragments (sAPPβ). Moreover, SNX7 overexpression caused a significant reduction of the steady-state levels of APP as well as of the cell surface APP levels. By using NH₄Cl and Bafilomycin A1 to inhibit the lysosomal degradative pathway, we found that the reduction of APP induced by SNX7 overexpression was prevented by such inhibition. No change in the cell surface distribution or steady-state levels of BACE1 was detected after overexpression of SNX7. Taken together, these results suggest that SNX7 regulates Aβ production by directing APP for degradation.