Presenilin-1-mediated retention of APP derivatives in early biosynthetic compartments.
Processing of the amyloid precursor protein (APP) leads to the production of amyloid-beta (Abeta), 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 Abeta formation, the gamma-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 beta-cleavage-derived APP-C-terminal fragment (CTFbeta) and/or Abeta in pre-Golgi membranes. Overexpression of PS-1 increased the percentage of CTFbeta and/or Abeta in VTCs as well as their distribution to COPI-coated VTC membranes. By contrast, overexpression of the dominant-negative aspartate mutant PS-1(D257A) or PS-knockout decreased incorporation of these APP derivatives into COPI-coated 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 gamma-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.
Réchards
Marloes
M
Cell Microscopy Center, Department of Cell Biology, University Medical Center and Institute for Biomembranes, 3584 CX Utrecht, the Netherlands.
Xia
Weiming
W
Oorschot
Viola
V
van Dijk
Suzanne
S
Annaert
Willem
W
Selkoe
Dennis J
DJ
Klumperman
Judith
J
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000096:biosynthesis / Q000648:ultrastructure; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism* / Q000648:ultrastructure; D000818:Animals; D016466:CHO Cells; D020755:Coat Protein Complex I / Q000378:metabolism / Q000648:ultrastructure; D006224:Cricetinae; D004622:Embryo, Mammalian; D004721:Endoplasmic Reticulum / Q000378:metabolism* / Q000648:ultrastructure; D011992:Endosomes / Q000378:metabolism / Q000648:ultrastructure; D005347:Fibroblasts / Q000378:metabolism / Q000648:ultrastructure; D006056:Golgi Apparatus / Q000378:metabolism* / Q000648:ultrastructure; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D051379:Mice; D018345:Mice, Knockout; D016253:Microscopy, Immunoelectron; D009154:Mutation; D010446:Peptide Fragments / Q000378:metabolism / Q000648:ultrastructure; D053764:Presenilin-1; D011499:Protein Processing, Post-Translational; D021381:Protein Transport
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D020755:Coat Protein Complex I; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1