title: A function for EHD family proteins in unidirectional retrograde dendritic transport of BACE1 and Alzheimer's disease Aβ production.
abstract: Abnormal accumulation of β-secretase (BACE1) in dystrophic neurites and presynaptic β-amyloid (Aβ) production contribute to Alzheimer's disease pathogenesis. Little, however, is known about BACE1 sorting and dynamic transport in neurons. We investigated BACE1 trafficking in hippocampal neurons using live-cell imaging and selective labeling. We report that transport vesicles containing internalized BACE1 in dendrites undergo exclusive retrograde transport toward the soma, whereas they undergo bidirectional transport in axons. Unidirectional dendritic transport requires Eps15-homology-domain-containing (EHD) 1 and 3 protein function. Furthermore, loss of EHD function compromises dynamic axonal transport and overall BACE1 levels in axons. EHD1/3 colocalize with BACE1 and APP β-C-terminal fragments in hippocampal mossy fiber terminals, and their depletion in neurons significantly attenuates Aβ levels. These results demonstrate unidirectional endocytic transport of a dendritic cargo and reveal a role for EHD proteins in neuronal BACE1 transcytosis and Aβ production, processes that are highly relevant for Alzheimer's disease.
authors.affiliation: Departments of Neurobiology, Neurology, and Pathology, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Virginie
authors.initials: V
authors.lastname: Buggia-Prévot
authors.affiliation: Committee on Neurobiology, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Celia G
authors.initials: CG
authors.lastname: Fernandez
authors.affiliation: Systems and Cell Biology of Neurodegeneration, Division of Psychiatry Research, University of Zurich, 8008 Zurich, Switzerland.
authors.forename: Vinod
authors.initials: V
authors.lastname: Udayar
authors.affiliation: Departments of Neurobiology, Neurology, and Pathology, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Kulandaivelu S
authors.initials: KS
authors.lastname: Vetrivel
authors.affiliation: Departments of Neurobiology, Neurology, and Pathology, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Aureliane
authors.initials: A
authors.lastname: Elie
authors.affiliation: Departments of Neurobiology, Neurology, and Pathology, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Jelita
authors.initials: J
authors.lastname: Roseman
authors.affiliation: Centre for Prions and Protein Folding Diseases, Departments of Medicine and Psychiatry, University of Alberta, Edmonton, AB T6G 2M8, Canada.
authors.forename: Verena A
authors.initials: VA
authors.lastname: Sasse
authors.affiliation: Committee on Neurobiology, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Margaret
authors.initials: M
authors.lastname: Lefkow
authors.affiliation: Departments of Neurobiology, Neurology, and Pathology, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Xavier
authors.initials: X
authors.lastname: Meckler
authors.affiliation: Eppley Institute for Research in Cancer and Allied Diseases and Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors.forename: Sohinee
authors.initials: S
authors.lastname: Bhattacharyya
authors.affiliation: Eppley Institute for Research in Cancer and Allied Diseases and Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors.forename: Manju
authors.initials: M
authors.lastname: George
authors.affiliation: Centre for Prions and Protein Folding Diseases, Departments of Medicine and Psychiatry, University of Alberta, Edmonton, AB T6G 2M8, Canada.
authors.forename: Satyabrata
authors.initials: S
authors.lastname: Kar
authors.affiliation: Department of Pharmacological and Physiological Sciences, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Vytautas P
authors.initials: VP
authors.lastname: Bindokas
authors.affiliation: Departments of Neurobiology, Neurology, and Pathology, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Angèle T
authors.initials: AT
authors.lastname: Parent
authors.affiliation: Systems and Cell Biology of Neurodegeneration, Division of Psychiatry Research, University of Zurich, 8008 Zurich, Switzerland.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Rajendran
authors.affiliation: Eppley Institute for Research in Cancer and Allied Diseases and Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors.forename: Hamid
authors.initials: H
authors.lastname: Band
authors.affiliation: Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Vassar
authors.affiliation: Departments of Neurobiology, Neurology, and Pathology, The University of Chicago, Chicago, IL 60637, USA; Committee on Neurobiology, The University of Chicago, Chicago, IL 60637, USA. Electronic address: gopal@uchicago.edu.
authors.forename: Gopal
authors.initials: G
authors.lastname: Thinakaran
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism*; D001370:Axonal Transport; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D003712:Dendrites / Q000378:metabolism*; D057809:HEK293 Cells; D006367:HeLa Cells; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D006801:Humans; D051379:Mice; D021381:Protein Transport; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D002352:Carrier Proteins; C485640:Ehd1 protein, mouse; C470993:Ehd3 protein, mouse; D033921:Vesicular Transport Proteins; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse