title: ADP ribosylation factor 6 (ARF6) controls amyloid precursor protein (APP) processing by mediating the endosomal sorting of BACE1.
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.
authors.affiliation: Laboratory of Membrane Trafficking, Center for Human Genetics, Catholic University of Leuven, Leuven, Belgium.
authors.forename: Ragna
authors.initials: R
authors.lastname: Sannerud
authors.forename: Ilse
authors.initials: I
authors.lastname: Declerck
authors.forename: Aleksandar
authors.initials: A
authors.lastname: Peric
authors.forename: Tim
authors.initials: T
authors.lastname: Raemaekers
authors.forename: Guillermo
authors.initials: G
authors.lastname: Menendez
authors.forename: Lujia
authors.initials: L
authors.lastname: Zhou
authors.forename: Baert
authors.initials: B
authors.lastname: Veerle
authors.forename: Katrijn
authors.initials: K
authors.lastname: Coen
authors.forename: Sebastian
authors.initials: S
authors.lastname: Munck
authors.forename: Bart
authors.initials: B
authors.lastname: De Strooper
authors.forename: Giampietro
authors.initials: G
authors.lastname: Schiavo
authors.forename: Wim
authors.initials: W
authors.lastname: Annaert
mesh_terms: D000089982:ADP-Ribosylation Factor 6; D020727:ADP-Ribosylation Factors / Q000378:metabolism*; D020816:Amino Acid Motifs; D053829:Amyloid Precursor Protein Secretases / Q000737:chemistry / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D018957:CD59 Antigens / Q000378:metabolism; D002451:Cell Compartmentation; D016764:Cell Polarity; D003712:Dendrites / Q000378:metabolism; D004705:Endocytosis; D011992:Endosomes / Q000201:enzymology*; D006367:HeLa Cells; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D006801:Humans; D007930:Leucine / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D051381:Rats; D011990:Receptors, Transferrin / Q000378:metabolism; D020691:rab GTP-Binding Proteins / Q000378:metabolism
chemical_list: D000089982:ADP-Ribosylation Factor 6; D016564:Amyloid beta-Protein Precursor; D018957:CD59 Antigens; D015395:Histocompatibility Antigens Class I; D011990:Receptors, Transferrin; D053829:Amyloid Precursor Protein Secretases; D020727:ADP-Ribosylation Factors; C000715348:ARF6 protein, human; C000715727:Arf6 protein, mouse; C000715349:Arf6 protein, rat; D020691:rab GTP-Binding Proteins; D007930:Leucine