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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U2 - 10.1016/j.celrep.2013.12.006
DO - 10.1016/j.celrep.2013.12.006
M3 - Article
C2 - 24373286
AN - SCOPUS:84890894103
SN - 2211-1247
VL - 5
SP - 1552
EP - 1563
JO - Cell Reports
JF - Cell Reports
IS - 6
ER -