Presenilin-1-mediated retention of APP derivatives in early biosynthetic compartments

Marloes Réchards, Weiming Xia, Viola Oorschot, Suzanne van Dijk, Willem Annaert, Dennis J. Selkoe, Judith Klumperman

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

Abstract

Processing of the amyloid precursor protein (APP) leads to the production of amyloid-β (Aβ), the major component of extracellular plaques in the brains of Alzheimer's disease (AD) patients. Presenilin-1 (PS-1) plays a key role in the final step of Aβ formation, the γ-secretase cleavage. Previously, we showed that PS-1 is retained in pre-Golgi compartments by incorporation into COPI-coated membranes of the vesicular tubular clusters (VTCs) between endoplasmic reticulum (ER) and Golgi complex. Here, we show that PS-1 also mediates the retention of the β-cleavage-derived APP-C-terminal fragment (CTFβ) and/or Aβ in pre-Golgi membranes. Overexpression of PS-1 increased the percentage of CTFβ and/or Aβ in VTCs as well as their distribution to COPI-coated VTC membranes. By contrast, overexpression of the dominant-negative aspartate mutant PS-1D257A or PS-knockout decreased incorporation of these APP derivatives into COPIcoated membranes. Sorting of APP derivatives to COPI-coated VTC membranes was not depending on the APP cytosolic tail. In post-Golgi compartments, PS-1 expression enhanced the association of full-length APP/APPs with endosomal compartments at the expense of plasma membrane-bound APP. We conclude that PS-1, in addition to its role in γ-secretase cleavage, is also required for the subcellular routing of APP and its derivatives. Malfunctioning of PS-1 in this role may have important consequences for the progress of AD.

Original languageEnglish (US)
Pages (from-to)354-364
Number of pages11
JournalTraffic
Volume7
Issue number3
DOIs
StatePublished - Mar 2006

Keywords

  • Alzheimer's disease
  • Amyloid precursor protein
  • COPI
  • Immunoelectron microscopy
  • Intermediate compartment
  • Membrane traffic
  • Presenilin-1

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Structural Biology
  • Molecular Biology
  • Genetics

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