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The levels of mature glycosylated nicastrin are regulated and correlate with γ‐secretase processing of amyloid β‐precursor protein
Author(s) -
Arawaka Shigeki,
Hasegawa Hiroshi,
Tandon Anurag,
Janus Christopher,
Chen Fusheng,
Yu Gang,
Kikuchi Kenji,
Koyama Shingo,
Kato Takeo,
Fraser Paul E.,
St GeorgeHyslop Peter
Publication year - 2002
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.2002.01207.x
Subject(s) - nicastrin , amyloid precursor protein , presenilin , microbiology and biotechnology , secretion , proteostasis , biochemistry , chemistry , amyloid precursor protein secretase , glycoprotein , biology , medicine , alzheimer's disease , disease
Nicastrin, a type‐I transmembrane glycoprotein, is a necessary component of the high molecular weight presenilin (PS) complexes that mediate intramembranous cleavage of β‐amyloid precursor protein (βAPP) 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 endoglycosidase‐H‐resistant forms of nicastrin on Aβ 40 ‐ and Aβ 42 ‐peptide secretion in several cell lines stably expressing a mutant nicastrin (D336A/Y337A) that increases Aβ secretion. There was no correlation between Aβ secretion and the level of over‐expression 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 Aβ secretion, but did not influence either βAPP trafficking or processing by α‐ and β‐secretases. Proper trafficking and terminal maturation of nicastrin is therefore a necessary event for the regulated intramembranous proteolysis of βAPP.