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 language | English (US) |
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Pages (from-to) | 354-364 |
Number of pages | 11 |
Journal | Traffic |
Volume | 7 |
Issue number | 3 |
DOIs | |
State | Published - 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