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Cell Rep. 2013 Dec 26;5(6):1552-63. doi: 10.1016/j.celrep.2013.12.006.

A function for EHD family proteins in unidirectional retrograde dendritic transport of BACE1 and Alzheimer's disease Aβ production.

Author information

1
Departments of Neurobiology, Neurology, and Pathology, The University of Chicago, Chicago, IL 60637, USA.
2
Committee on Neurobiology, The University of Chicago, Chicago, IL 60637, USA.
3
Systems and Cell Biology of Neurodegeneration, Division of Psychiatry Research, University of Zurich, 8008 Zurich, Switzerland.
4
Centre for Prions and Protein Folding Diseases, Departments of Medicine and Psychiatry, University of Alberta, Edmonton, AB T6G 2M8, Canada.
5
Eppley Institute for Research in Cancer and Allied Diseases and Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA.
6
Department of Pharmacological and Physiological Sciences, The University of Chicago, Chicago, IL 60637, USA.
7
Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
8
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.

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.

PMID:
24373286
PMCID:
PMC3932704
DOI:
10.1016/j.celrep.2013.12.006
[Indexed for MEDLINE]
Free PMC Article

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