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.
Cell Microscopy Center, Department of Cell Biology, University Medical Center and Institute for Biomembranes, 3584 CX Utrecht, the Netherlands.
Marloes
M
Réchards
Weiming
W
Xia
Viola
V
Oorschot
Suzanne
S
van Dijk
Willem
W
Annaert
Dennis J
DJ
Selkoe
Judith
J
Klumperman
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