title: Retromer regulates postendocytic sorting of β-secretase in polarized Madin-Darby canine kidney cells.
abstract: β-Amyloid (Aβ) peptides are generated from the successive proteolytic processing of the amyloid precursor protein (APP) by the β-APP cleaving enzyme (BACE or β-secretase) and the γ-secretase complex. Initial cleavage of APP by BACE leads into the amyloidogenic pathway, causing or exacerbating Alzheimer's disease. Therefore, their intracellular traffic can determine how easily and frequently BACE has access to and cleaves APP. Here, we have used polarized Madin-Darby canine kidney (MDCK) cells stably expressing APP and BACE to examine the regulation of their polarized trafficking by retromer, a protein complex previously implicated in their endosome-to-Golgi transport. Our data show that retromer interacts with BACE and regulates its postendocytic sorting in polarized MDCK cells. Depleting retromer, inhibiting retromer function, or preventing BACE interaction with retromer, alters trafficking of BACE, which thereby increases its localization in the early endocytic compartment. As a result, this slows endocytosis of apically localized BACE, promoting its recycling and apical-to-basolateral transcytosis, which increases APP/BACE interaction and subsequent cleavage of APP toward generation and secretion of Aβ peptides.
authors: Laboratory of Epithelial Cell Biology, Centro de Investigación Príncipe Felipe, Valencia, Spain.
authors: Yasmina
authors: Y
authors: Cuartero
authors: Maravillas
authors: M
authors: Mellado
authors: Anja
authors: A
authors: Capell
authors: Manuel
authors: M
authors: Alvarez-Dolado
authors: Marcel
authors: M
authors: Verges
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D004285:Dogs; D004705:Endocytosis; D011992:Endosomes / Q000378:metabolism; D006056:Golgi Apparatus / Q000378:metabolism; D061985:Madin Darby Canine Kidney Cells; D051379:Mice; D046912:Multiprotein Complexes / Q000378:metabolism; D009154:Mutation; D054730:Protein Interaction Domains and Motifs; D021381:Protein Transport; D033921:Vesicular Transport Proteins / Q000378:metabolism*
chemical_list: D016564:Amyloid beta-Protein Precursor; D046912:Multiprotein Complexes; D033921:Vesicular Transport Proteins; D053829:Amyloid Precursor Protein Secretases