A Function for EHD Family Proteins in Unidirectional Retrograde Dendritic Transport of BACE1 and Alzheimer’s Disease Aβ Production
Virginie Buggia-Prévot,
Celia G. Fernandez,
Vinod Udayar,
Kulandaivelu S. Vetrivel,
Aureliane Elie,
Jelita Roseman,
Verena A. Sasse,
Margaret Lefkow,
Xavier Meckler,
Sohinee Bhattacharyya,
Manju George,
Satyabrata Kar,
Vytautas P. Bindokas,
Angèle T. Parent,
Lawrence Rajendran,
Hamid Band,
Robert Vassar,
Gopal Thinakaran
Affiliations
Virginie Buggia-Prévot
Departments of Neurobiology, Neurology, and Pathology, The University of Chicago, Chicago, IL 60637, USA
Celia G. Fernandez
Committee on Neurobiology, The University of Chicago, Chicago, IL 60637, USA
Vinod Udayar
Systems and Cell Biology of Neurodegeneration, Division of Psychiatry Research, University of Zurich, 8008 Zurich, Switzerland
Kulandaivelu S. Vetrivel
Departments of Neurobiology, Neurology, and Pathology, The University of Chicago, Chicago, IL 60637, USA
Aureliane Elie
Departments of Neurobiology, Neurology, and Pathology, The University of Chicago, Chicago, IL 60637, USA
Jelita Roseman
Departments of Neurobiology, Neurology, and Pathology, The University of Chicago, Chicago, IL 60637, USA
Verena A. Sasse
Centre for Prions and Protein Folding Diseases, Departments of Medicine and Psychiatry, University of Alberta, Edmonton, AB T6G 2M8, Canada
Margaret Lefkow
Committee on Neurobiology, The University of Chicago, Chicago, IL 60637, USA
Xavier Meckler
Departments of Neurobiology, Neurology, and Pathology, The University of Chicago, Chicago, IL 60637, USA
Sohinee Bhattacharyya
Eppley Institute for Research in Cancer and Allied Diseases and Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA
Manju George
Eppley Institute for Research in Cancer and Allied Diseases and Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA
Satyabrata Kar
Centre for Prions and Protein Folding Diseases, Departments of Medicine and Psychiatry, University of Alberta, Edmonton, AB T6G 2M8, Canada
Vytautas P. Bindokas
Department of Pharmacological and Physiological Sciences, The University of Chicago, Chicago, IL 60637, USA
Angèle T. Parent
Departments of Neurobiology, Neurology, and Pathology, The University of Chicago, Chicago, IL 60637, USA
Lawrence Rajendran
Systems and Cell Biology of Neurodegeneration, Division of Psychiatry Research, University of Zurich, 8008 Zurich, Switzerland
Hamid Band
Eppley Institute for Research in Cancer and Allied Diseases and Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA
Robert Vassar
Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
Gopal Thinakaran
Departments of Neurobiology, Neurology, and Pathology, The University of Chicago, Chicago, IL 60637, USA
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.
