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

Research output: Contribution to journalArticle

43 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1552-1563
Number of pages12
JournalCell Reports
Volume5
Issue number6
DOIs
StatePublished - Dec 26 2013

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Buggia-Prévot, V., Fernandez, C. G., Udayar, V., Vetrivel, K. S., Elie, A., Roseman, J., Sasse, V. A., Lefkow, M., Meckler, X., Bhattacharyya, S., George, M., Kar, S., Bindokas, V. P., Parent, A. T., Rajendran, L., Band, H., Vassar, R., & Thinakaran, G. (2013). A function for EHD family proteins in unidirectional retrograde dendritic transport of BACE1 and alzheimer's disease Aβ production. Cell Reports, 5(6), 1552-1563. https://doi.org/10.1016/j.celrep.2013.12.006