TY - JOUR
T1 - Axonal BACE1 dynamics and targeting in hippocampal neurons
T2 - A role for Rab11 GTPase
AU - Buggia-Prévot, Virginie
AU - Fernandez, Celia G.
AU - Riordan, Sean
AU - Vetrivel, Kulandaivelu S.
AU - Roseman, Jelita
AU - Waters, Jack
AU - Bindokas, Vytautas P.
AU - Vassar, Robert
AU - Thinakaran, Gopal
N1 - Funding Information:
This work was supported by grants from the National Institutes of Health (AG019070 and AG021495 to G.T.; AG022560 and AG030142 to R.V.; Cure Alzheimer’s Fund (G.T. and B.V.), BrightFocus Foundation (G.T.), and Alzheimer’s Association (G.T.). V.B-P. was partially supported by a fellowship from Alzheimer’s Disease Research Fund of Illinois Department of Public Health. C.G.F. was 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 S10OD010649), and Northwestern University Cell Imaging Facility (supported by NCI CCSG P30 CA060553). We thank James Lopez, Multiphoton Specialist at Olympus for assistance with brain slice imaging.
PY - 2014/1/4
Y1 - 2014/1/4
N2 - Background: BACE1 is one of the two enzymes that cleave amyloid precursor protein to generate Alzheimer's disease (AD) beta amyloid peptides. It is widely believed that BACE1 initiates APP processing in endosomes, and in the brain this cleavage is known to occur during axonal transport of APP. In addition, BACE1 accumulates in dystrophic neurites surrounding brain senile plaques in individuals with AD, suggesting that abnormal accumulation of BACE1 at presynaptic terminals contributes to pathogenesis in AD. However, only limited information is available on BACE1 axonal transport and targeting. Results: By visualizing BACE1-YFP dynamics using live imaging, we demonstrate that BACE1 undergoes bi-directional transport in dynamic tubulo-vesicular carriers along axons in cultured hippocampal neurons and in acute hippocampal slices of transgenic mice. In addition, a subset of BACE1 is present in larger stationary structures, which are active presynaptic sites. In cultured neurons, BACE1-YFP is preferentially targeted to axons over time, consistent with predominant in vivo localization of BACE1 in presynaptic terminals. Confocal analysis and dual-color live imaging revealed a localization and dynamic transport of BACE1 along dendrites and axons in Rab11-positive recycling endosomes. Impairment of Rab11 function leads to a diminution of total and endocytosed BACE1 in axons, concomitant with an increase in the soma. Together, these results suggest that BACE1 is sorted to axons in endosomes in a Rab11-dependent manner. Conclusion: Our results reveal novel information on dynamic BACE1 transport in neurons, and demonstrate that Rab11-GTPase function is critical for axonal sorting of BACE1. Thus, we suggest that BACE1 transcytosis in endosomes contributes to presynaptic BACE1 localization.
AB - Background: BACE1 is one of the two enzymes that cleave amyloid precursor protein to generate Alzheimer's disease (AD) beta amyloid peptides. It is widely believed that BACE1 initiates APP processing in endosomes, and in the brain this cleavage is known to occur during axonal transport of APP. In addition, BACE1 accumulates in dystrophic neurites surrounding brain senile plaques in individuals with AD, suggesting that abnormal accumulation of BACE1 at presynaptic terminals contributes to pathogenesis in AD. However, only limited information is available on BACE1 axonal transport and targeting. Results: By visualizing BACE1-YFP dynamics using live imaging, we demonstrate that BACE1 undergoes bi-directional transport in dynamic tubulo-vesicular carriers along axons in cultured hippocampal neurons and in acute hippocampal slices of transgenic mice. In addition, a subset of BACE1 is present in larger stationary structures, which are active presynaptic sites. In cultured neurons, BACE1-YFP is preferentially targeted to axons over time, consistent with predominant in vivo localization of BACE1 in presynaptic terminals. Confocal analysis and dual-color live imaging revealed a localization and dynamic transport of BACE1 along dendrites and axons in Rab11-positive recycling endosomes. Impairment of Rab11 function leads to a diminution of total and endocytosed BACE1 in axons, concomitant with an increase in the soma. Together, these results suggest that BACE1 is sorted to axons in endosomes in a Rab11-dependent manner. Conclusion: Our results reveal novel information on dynamic BACE1 transport in neurons, and demonstrate that Rab11-GTPase function is critical for axonal sorting of BACE1. Thus, we suggest that BACE1 transcytosis in endosomes contributes to presynaptic BACE1 localization.
KW - Axonal sorting
KW - Axonal transport
KW - BACE1
KW - Rab11
KW - Recycling endosome
KW - Transcytosis
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U2 - 10.1186/1750-1326-9-1
DO - 10.1186/1750-1326-9-1
M3 - Article
C2 - 24386896
AN - SCOPUS:84891551438
SN - 1750-1326
VL - 9
JO - Molecular Neurodegeneration
JF - Molecular Neurodegeneration
IS - 1
M1 - 1
ER -