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Presenilin‐1‐mediated Retention of APP Derivatives in Early Biosynthetic Compartments
Author(s) -
Réchards Marloes,
Xia Weiming,
Oorschot Viola,
van Dijk Suzanne,
Annaert Willem,
Selkoe Dennis J.,
Klumperman Judith
Publication year - 2006
Publication title -
traffic
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.677
H-Index - 130
eISSN - 1600-0854
pISSN - 1398-9219
DOI - 10.1111/j.1600-0854.2006.00388.x
Subject(s) - copi , golgi apparatus , endoplasmic reticulum , endosome , presenilin , microbiology and biotechnology , amyloid precursor protein , biology , cellular compartment , subcellular localization , cytosol , membrane , secretory pathway , biochemistry , alzheimer's disease , cytoplasm , intracellular , cell , enzyme , disease , pathology , medicine
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‐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 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.