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

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,...

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Bibliographic Details
Published in:Molecular neurodegeneration 2014-01, Vol.9 (1), p.1-1, Article 1
Main Authors: Buggia-Prévot, Virginie, Fernandez, Celia G, Riordan, Sean, Vetrivel, Kulandaivelu S, Roseman, Jelita, Waters, Jack, Bindokas, Vytautas P, Vassar, Robert, Thinakaran, Gopal
Format: Article
Language:English
Subjects:
Advertising executives
Alzheimer's disease
Amyloid Precursor Protein Secretases - metabolism
Animals
Aspartic Acid Endopeptidases - metabolism
Axonal Transport - physiology
Axons - metabolism
Binding sites
Brain
Colleges & universities
Complications and side effects
Development and progression
Endosomes - metabolism
Enzymes
Hippocampus - metabolism
Immunohistochemistry
Mice
Mice, Transgenic
Microscopy
Microscopy, Confocal
Neurons
Neurons - metabolism
Neurosciences
Organ Culture Techniques
Patient outcomes
Physiological aspects
Proteins
rab GTP-Binding Proteins - metabolism
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Summary: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. 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. 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.
ISSN:1750-1326
1750-1326
DOI:10.1186/1750-1326-9-1