Axonal BACE1 dynamics and targeting in hippocampal neurons: a role for Rab11 GTPase.
Axonal BACE1 dynamics and targeting in hippocampal neurons: a role for Rab11 GTPase.
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DOI：
10.1186/1750-1326-9-1
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发表时间：
2014-01-04
影响因子：
15.1
通讯作者：
Thinakaran G
中科院分区：
文献类型：
--
作者：
Buggia-Prévot V;Fernandez CG;Riordan S;Vetrivel KS;Roseman J;Waters J;Bindokas VP;Vassar R;Thinakaran G
BACE1是切割淀粉样蛋白前体蛋白以产生阿尔茨海默病(AD) β淀粉样肽的两种酶之一。人们普遍认为，BACE1在内体中启动APP加工，在大脑中，这种切割已知发生在APP的轴突运输过程中。此外，BACE1在AD患者脑老年斑周围的营养不良神经突中积累，表明BACE1在突触前末端的异常积累参与了AD的发病机制。然而，关于BACE1轴突转运和靶向的信息有限。通过实时成像可视化BACE1- yfp的动态，我们证明BACE1在培养的海马神经元和转基因小鼠的急性海马切片中沿着轴突在动态小管-囊泡载体中进行双向运输。此外，BACE1的一个子集存在于较大的固定结构中，这些结构是活跃的突触前位点。在培养的神经元中，随着时间的推移，BACE1- yfp优先靶向轴突，这与BACE1在突触前终末的主要体内定位一致。共聚焦分析和双色实时成像显示BACE1沿rab11阳性循环核内体的树突和轴突定位和动态运输。Rab11功能的损伤导致轴突中总BACE1和内吞BACE1的减少，并伴随胞体的增加。综上所述，这些结果表明BACE1以rab11依赖的方式在核内体中被分类到轴突上。我们的研究结果揭示了BACE1在神经元中动态转运的新信息，并证明Rab11-GTPase功能对BACE1的轴突分选至关重要。因此，我们认为内体中的BACE1胞吞作用有助于突触前BACE1的定位。
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.
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通讯作者：
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通讯作者：
Thinakaran G