Nicastrin has a key role in the regulation of presenilin-mediated cleavage of the b-amyloid precursor protein (b-APP) and Notch/GLP-1. Nicastrin binds to the membrane-tethered form of Notch and is essential for the intramembrane cleavage of Notch to generate Notch intracellular domain (NICD), which is involved in intracellular signaling. It has been suggested that nicastrin binds substrates of presenilin/g-secretase complexes or modulates g-secretase activity. Suppression of nicastrin expression in C. elegansembryos induces a subset of notch/glp-1 phenotypes similar to those induced by simultaneous null mutations in both presenilin homologues of C. elegans (sel-12 and hop-1). Thus, increasing evidence indicates that both nicastrin and presenilins are necessary components for the intramembrane proteolysis of proteins such as b-APP and Notch, and implicates a direct role for nicastrin in the pathogenesis of Alzheimer′s disease and in the regulation of Notch signaling in vivo.
