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Title: ADP ribosylation factor 6 (ARF6) controls amyloid precursor protein (APP) processing by mediating the endosomal sorting of BACE1
Authors: Sannerud, Ragna ×
Declerck, Ilse
Peric, Aleksandar
Raemaekers, Tim
Menendez, Guillermo
Zhou, Lujia
Veerle, Baert
Coen, Katrijn
Munck, Sebastian
De Strooper, Bart
Schiavo, Giampietro
Annaert, Wim #
Issue Date: Aug-2011
Publisher: National Academy of Sciences
Series Title: Proceedings of the National Academy of Sciences of the United States of America vol:108 issue:34 pages:E559-E568
Abstract: Amyloid β (Aβ) peptides, the primary constituents of senile plaques and a hallmark in Alzheimer's disease pathology, are generated through the sequential cleavage of amyloid precursor protein (APP) by β-site APP cleaving enzyme 1 (BACE1) and γ-secretase. The early endosome is thought to represent a major compartment for APP processing; however, the mechanisms of how BACE1 encounters APP are largely unknown. In contrast to APP internalization, which is clathrin-dependent, we demonstrate that BACE1 is sorted to early endosomes via a route controlled by the small GTPase ADP ribosylation factor 6 (ARF6). Altering ARF6 levels or its activity affects endosomal sorting of BACE1, and consequently results in altered APP processing and Aβ production. Furthermore, sorting of newly internalized BACE1 from ARF6-positive towards RAB GTPase 5 (RAB5)-positive early endosomes depends on its carboxyterminal short acidic cluster-dileucine motif. This ARF6-mediated sorting of BACE1 is confined to the somatodendritic compartment of polarized neurons in agreement with Aβ peptides being primarily secreted from here. These results demonstrate a spatial separation between APP and BACE1 during surface-to-endosome transport, suggesting subcellular trafficking as a regulatory mechanism for this proteolytic processing step. It thereby provides a novel avenue to interfere with Aβ production through a selective modulation of the distinct endosomal transport routes used by BACE1 or APP.
URI: 
ISSN: 0027-8424
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Biomedical Sciences Group Management - miscellaneous
Laboratory of Membrane Trafficking
Laboratory for the Research of Neurodegenerative Diseases
Department of Human Genetics - miscellaneous
× corresponding author
# (joint) last author

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