Axonal BACE1 dynamics and targeting in hippocampal neurons: a role for Rab11 GTPase

Molecular Neurodegeneration

Gopal Thinakaran¹  Robert Vassar²  Vytautas P Bindokas⁴  Jack Waters³  Jelita Roseman⁵  Kulandaivelu S Vetrivel⁵  Sean Riordan²  Celia G Fernandez¹  Virginie Buggia-Prévot⁵ 

[1] Committee on Neurobiology, The University of Chicago, Chicago, IL 60637, USA;Department of Cell and Molecular Biology, Northwestern University, Chicago, IL 60611, USA;Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA;Department Neurobiology, Pharmacology and Physiology, The University of Chicago, Chicago, IL 60637, USA;Department of Pathology, The University of Chicago, Chicago, IL 60637, USA

关键词: Recycling endosome;    Axonal transport;    Axonal sorting;    Transcytosis;    Rab11;    BACE1;   

Others  :  861927
DOI  :  10.1186/1750-1326-9-1

 received in 2013-11-22, accepted in 2013-12-22,  发布年份 2014

【 摘 要 】

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.

【 授权许可】

   
2014 Buggia-Prévot et al.; licensee BioMed Central Ltd.

【 图 表 】

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