Nicastrin modulates presenilin-mediated notch/glp-1 signal transduction and beta APP processing

Nicastrin, a transmembrane glycoprotein, forms high molecular weight comple xes with presenilin 1 and presenilin 2. Suppression of nicastrin expression in Caenorhabditis elegans embryos induces a subset of notch/glp-1 phenotyp es similar to those induced by simultaneous null mutations in both presenil in homologues of C. elegans(sel-12 and hop-1). Nicastrin also binds carboxy -terminal derivatives of beta-amyloid precursor protein (beta APP), and mod ulates the production of the amyloid beta-peptide (A beta) from these deriv atives. Missense mutations in a conserved hydrophilic domain of nicastrin i ncrease A beta(42) and A beta(40) peptide secretion. Deletions in this doma in inhibit A beta production. Nicastrin and presenilins are therefore likel y to be functional components of a multimeric complex necessary for the int ramembranous proteolysis of proteins such as Notch/GLP-1 and beta APP.