Presenilin 1 mutations influence processing and trafficking of the ApoE receptor apoER2

Schematic illustration of apoER2 processing at the membrane. ApoER2 is a type I transmembrane protein. Cleavage by sheddase produces secreted apoER2 ectodomain and C-terminal fragment designated as “SR” (sheddase remnant). The latter is further processed within the transmembrane region by γ-secretase (presenillin 1, PS1), releasing C-terminal fragment (γ-CTF). DAPT, a γ-secretase inihibitor blocks the intramembrane cleavage. ApoER2 is bound by ligands such as ApoE and Reelin, the latter of which enhances proteolytic processing at both sites of apoER2 on binding. We find that mutations in PS1 associated with inheritance of Alzhemier's disease attenuate cleavage of SR and the formation of γ-CTF.91