The levels of, mature glycosylated nicastrin are regulated and correlate with γ-secretase processing of amyloid β-precursor protein

Nicastrin, a typed transmembrane glycoprotein, is a necessary Component of the high molecular weight presenilin (PS) complexes that mediate intramembranous cleavage of beta-amyloid precursor protein (betaAPP) and Notch. Nicastrin undergoes trafficking-dependent glycosylation maturation, and PS1 interacts preferentially, with these maturely glycosylated forms,of nicastrin. We investigated the effects of differing levels of the immature and mature endoglycosiclase-H-resistant forms of nicastrin on Abeta(40)- and Abeta(42)-peptide secretion in several cell lines stably expressing a mutant nicastrin (D336A/Y337A) that increases Abeta secretion. There was no correlation between Abeta secretion and the level of overexpression of the immature forms of nicastrin. The total level of mature nicastrin remained constant, but mutant nicastrin replaced endogenous mature nicastrin in varying degrees. Differences in the levels of mature mutant nicastrin positively correlated with Abeta secretion, but did not influence either PAPP trafficking or processing by alpha- and beta-secretases. Proper trafficking and terminal maturation of nicastrin is therefore a necessary event for the regulated intramembranous proteolysis of betaAPP.