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

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

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^*

^*Corresponding author for this work

Neurology

Research output: Contribution to journal › Article › peer-review

59 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 language	English (US)
Pages (from-to)	1552-1563
Number of pages	12
Journal	Cell reports
Volume	5
Issue number	6
DOIs	https://doi.org/10.1016/j.celrep.2013.12.006
State	Published - Dec 26 2013

Funding

We thank Drs. Sangram, S. Sisodia, Kamal Sharma, Marie-Claude Potier, and Vladimir I. Gelfand for helpful discussions. This work was supported by grants from the National Institutes of Health (AG019070 and AG021495 to G.T.; AG022560 and AG030142 to R.V.; CA105489, CA99163, CA87986, and CA116552 to H.B.; and NS055223 to A.T.P.), Cure Alzheimer’s Fund (G.T. and R.V.), BrightFocus Foundation (G.T.), and Alzheimer’s Association (G.T.). L.R. was supported by the Swiss National Science Foundation, the Velux Foundation, Bangerter Stiftung, Baugarten Stiftung, and the Novartis Foundation. L.R. and V.U. were supported by the European Neuroscience Campus of the Erasmus Mundus Program. V.B.-P. was partially supported by a fellowship from Alzheimer’s Disease Research Fund of Illinois Department of Public Health. C.G.F. and M.L. were supported by National Institute of General Medical Sciences training grant GM07839-30. Confocal imaging was performed at the Integrated Microscopy Core Facility at the University of Chicago (supported by S10 OD010649).

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.celrep.2013.12.006

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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

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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.",

author = "Virginie Buggia-Pr{\'e}vot and Fernandez, {Celia G.} and Vinod Udayar and Vetrivel, {Kulandaivelu S.} and Aureliane Elie and Jelita Roseman and Sasse, {Verena A.} and Margaret Lefkow and Xavier Meckler and Sohinee Bhattacharyya and Manju George and Satyabrata Kar and Bindokas, {Vytautas P.} and Parent, {Ang{\`e}le T.} and Lawrence Rajendran and Hamid Band and Robert Vassar and Gopal Thinakaran",

note = "Funding Information: We thank Drs. Sangram, S. Sisodia, Kamal Sharma, Marie-Claude Potier, and Vladimir I. Gelfand for helpful discussions. This work was supported by grants from the National Institutes of Health (AG019070 and AG021495 to G.T.; AG022560 and AG030142 to R.V.; CA105489, CA99163, CA87986, and CA116552 to H.B.; and NS055223 to A.T.P.), Cure Alzheimer{\textquoteright}s Fund (G.T. and R.V.), BrightFocus Foundation (G.T.), and Alzheimer{\textquoteright}s Association (G.T.). L.R. was supported by the Swiss National Science Foundation, the Velux Foundation, Bangerter Stiftung, Baugarten Stiftung, and the Novartis Foundation. L.R. and V.U. were supported by the European Neuroscience Campus of the Erasmus Mundus Program. V.B.-P. was partially supported by a fellowship from Alzheimer{\textquoteright}s Disease Research Fund of Illinois Department of Public Health. C.G.F. and M.L. were supported by National Institute of General Medical Sciences training grant GM07839-30. Confocal imaging was performed at the Integrated Microscopy Core Facility at the University of Chicago (supported by S10 OD010649). ",

year = "2013",

month = dec,

day = "26",

doi = "10.1016/j.celrep.2013.12.006",

language = "English (US)",

volume = "5",

pages = "1552--1563",

journal = "Cell reports",

issn = "2211-1247",

publisher = "Cell Press",

number = "6",

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Buggia-Prévot, V, Fernandez, CG, Udayar, V, Vetrivel, KS, Elie, A, Roseman, J, Sasse, VA, Lefkow, M, Meckler, X, Bhattacharyya, S, George, M, Kar, S, Bindokas, VP, Parent, AT, 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, vol. 5, no. 6, pp. 1552-1563. https://doi.org/10.1016/j.celrep.2013.12.006

TY - JOUR

T1 - A function for EHD family proteins in unidirectional retrograde dendritic transport of BACE1 and alzheimer's disease Aβ production

AU - Buggia-Prévot, Virginie

AU - Fernandez, Celia G.

AU - Udayar, Vinod

AU - Vetrivel, Kulandaivelu S.

AU - Elie, Aureliane

AU - Roseman, Jelita

AU - Sasse, Verena A.

AU - Lefkow, Margaret

AU - Meckler, Xavier

AU - Bhattacharyya, Sohinee

AU - George, Manju

AU - Kar, Satyabrata

AU - Bindokas, Vytautas P.

AU - Parent, Angèle T.

AU - Rajendran, Lawrence

AU - Band, Hamid

AU - Vassar, Robert

AU - Thinakaran, Gopal

N1 - Funding Information: We thank Drs. Sangram, S. Sisodia, Kamal Sharma, Marie-Claude Potier, and Vladimir I. Gelfand for helpful discussions. This work was supported by grants from the National Institutes of Health (AG019070 and AG021495 to G.T.; AG022560 and AG030142 to R.V.; CA105489, CA99163, CA87986, and CA116552 to H.B.; and NS055223 to A.T.P.), Cure Alzheimer’s Fund (G.T. and R.V.), BrightFocus Foundation (G.T.), and Alzheimer’s Association (G.T.). L.R. was supported by the Swiss National Science Foundation, the Velux Foundation, Bangerter Stiftung, Baugarten Stiftung, and the Novartis Foundation. L.R. and V.U. were supported by the European Neuroscience Campus of the Erasmus Mundus Program. V.B.-P. was partially supported by a fellowship from Alzheimer’s Disease Research Fund of Illinois Department of Public Health. C.G.F. and M.L. were supported by National Institute of General Medical Sciences training grant GM07839-30. Confocal imaging was performed at the Integrated Microscopy Core Facility at the University of Chicago (supported by S10 OD010649).

PY - 2013/12/26

Y1 - 2013/12/26

N2 - 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.

AB - 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.

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UR - http://www.scopus.com/inward/citedby.url?scp=84890894103&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2013.12.006

DO - 10.1016/j.celrep.2013.12.006

M3 - Article

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AN - SCOPUS:84890894103

SN - 2211-1247

VL - 5

SP - 1552

EP - 1563

JO - Cell reports

JF - Cell reports

IS - 6

ER -

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

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