Cholesterol-depletion corrects APP and BACE1 misstrafficking in NPC1-deficient cells

►We examine the mechanism of increased β-secretase processing of APP in NPC1−/− cells. ►APP internalization is prerequisite for increased Aβ/APP-CTF levels in NPC1−/− cells. ►Upon NPC1-loss APP and BACE1 (β-secretase) sequester within endocytic vesicles. ►Cholesterol-depletion corrects APP and BACE1 misstrafficking in NPC1−/− cells. ►Cholesterol modulates Alzheimer's disease by altering trafficking of APP and BACE1.