Cellular localization of Nicastrin affects amyloid β species production

The γ-secretase complex, composed by presenilin, nicastrin, APH-1 and PEN-2, is involved in intramembranous proteolysis of membrane proteins, such as amyloid precursor protein or Notch. Cleavage occurs in multiple cellular compartments. Here, nicastrin mutants containing targeting signals to the endoplasmic reticulum, trans-Golgi network, lysosomes, or plasma membrane have been shown to yield active γ-secretase complexes with different activities and specificities: wild-type and plasma membrane nicastrin complexes yielded the highest amounts of secreted amyloid-β peptide (Aβ), predominantly Aβ40, whereas intracellular targeted mutants produced intracellular Aβ, with a comparatively higher amount of Aβ42. These results suggest that compartmental microenvironments play a role in γ-secretase activity and specificity.