Carboxyl-terminal fragments of alzheimer β-amlyloid precursor protein accumulate in restricted and unpredicted intracellular compartments in presenilin 1-deficient cells

Fusheng Chen, Dun Sheng Yang, Suzana Petanceska, Austin Yang, Anurag Tandon, Gang Yu, Richard Rozmahel, Jorge Ghiso, Masaki Nishimura, Dong Mei Zhang, Toshitaka Kawarai, Georges Levesque, Julia Mills, Lyne Levesque, You Qiang Song, Ekaterina Rogaeva, David Westaway, Howard Mount, Sam Gandy, Peter St. George-HyslopPaul E. Fraser

Research output: Contribution to journalArticlepeer-review

67 Scopus citations

Abstract

Absence of functional presenilin 1 (PS1) protein leads to loss of γ-secretase cleavage of the amyloid precursor protein (βAPP), resulting in a dramatic reduction in amyloid β peptide (Aβ) production and accumulation of α- or β-secretase-cleaved COOH-terminal fragments of βAPP (α- or β-CTFs). The major COOH-terminal fragment (CTF) in brain was identified as αAPP-CTF-(11-98), which is consistent with the observation that cultured neurons generate primarily Aβ-(11-40). In PS1(-/-) murine neurons and fibroblasts expressing the loss-of-function PS1(D385A) mutant, CTFs accumulated in the endoplasmic reticulum, Golgi, and lysosomes, but not late endosomes. There were some subtle differences in the subcellular distribution of CTFs in PS1(-/-) neurons as compared with PS1(D385A) mutant fibroblasts. However, there was no obvious redistribution of full-length βAPP or of markers of other organelles in either mutant. Blockade of endoplasmic reticulum-to-Golgi trafficking indicated that in PS1(-/-) neurons (as in normal cells) trafficking of βAPP to the Golgi compartment is necessary before α- and β-secretase cleavages occur. Thus, although we cannot exclude a specific role for PS1 in trafficking of CTFs, these data argue against a major role in general protein trafficking. These results are more compatible with a role for PS1 either as the actual γ-secretase catalytic activity or in other functions indirectly related to γ-secretase catalysis (e.g. an activator of γ-secretase, a substrate adaptor for γ-secretase, or delivery of γ-secretase to βAPP-containing compartments).

Original languageEnglish (US)
Pages (from-to)36794-36802
Number of pages9
JournalJournal of Biological Chemistry
Volume275
Issue number47
DOIs
StatePublished - Nov 24 2000

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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