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

Shigeki Arawaka, Hiroshi Hasegawa, Anurag Tandon, Christopher Janus, Fusheng Chen, Gang Yu, Kenji Kikuchi, Shingo Koyama, Takeo Kato, Paul E. Fraser, Peter St George-Hyslop

Research output: Contribution to journalArticle

33 Scopus citations

Abstract

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 Aβ40- and Aβ42-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.

Original languageEnglish (US)
Pages (from-to)1065-1071
Number of pages7
JournalJournal of Neurochemistry
Volume83
Issue number5
DOIs
StatePublished - Dec 1 2002

Keywords

  • Nicastrin
  • Notch
  • Presenilin
  • Secretase
  • β-amyloid precursor protein

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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    Arawaka, S., Hasegawa, H., Tandon, A., Janus, C., Chen, F., Yu, G., Kikuchi, K., Koyama, S., Kato, T., Fraser, P. E., & St George-Hyslop, P. (2002). The levels of mature glycosylated nicastrin are regulated and correlate with γ-secretase processing of amyloid β-precursor protein. Journal of Neurochemistry, 83(5), 1065-1071. https://doi.org/10.1046/j.1471-4159.2002.01207.x