Sabo Shasta L, Ikin Annat F, Buxbaum Joseph D, Greengard Paul
Laboratory of Molecular and Cellular Neuroscience and the Zachary and Elizabeth M. Fisher Center, The Rockefeller University, New York, New York 10021, USA.
J Neurosci. 2003 Jul 2;23(13):5407-15. doi: 10.1523/JNEUROSCI.23-13-05407.2003.
Although the Alzheimer amyloid protein precursor (APP) has been studied intensely for more than a decade, its function in neurons is unresolved. Much less is known about its binding partner FE65. We have shown recently that APP and FE65 synergistically regulate the movement of transfected cells. It remained to be shown whether endogenous APP and FE65 could play a similar role in vivo. Here, we show that FE65, like APP, is expressed at high levels in neurons. Using a combination of immunofluorescence, live imaging, and subcellular fractionation, we find that FE65 and APP localize in vitro and in vivo to the most motile regions of neurons, the growth cones. Within growth cones, APP and FE65 concentrate in actin-rich lamellipodia. Finally, APP and FE65 interact in nerve terminals, where they associate with Rab5-containing synaptic organelles but not with synaptic vesicles. Our data are consistent with a role for the APP/FE65 complex in regulation of actin-based membrane motility in neurons, which could be important for highly dynamic processes such as neurite growth and synapse modification.
尽管阿尔茨海默病淀粉样蛋白前体（APP）已经被深入研究了十多年，但其在神经元中的功能仍未明确。对于其结合伴侣FE65的了解则更少。我们最近发现APP和FE65协同调节转染细胞的运动。内源性APP和FE65在体内是否能发挥类似作用仍有待证实。在此，我们表明，与APP一样，FE65在神经元中高水平表达。通过结合免疫荧光、实时成像和亚细胞分级分离技术，我们发现FE65和APP在体外和体内均定位于神经元最具运动性的区域——生长锥。在生长锥内，APP和FE65集中在富含肌动蛋白的片状伪足中。最后，APP和FE65在神经末梢相互作用，它们与含有Rab5的突触细胞器相关联，但不与突触小泡相关联。我们的数据与APP/FE65复合物在调节神经元中基于肌动蛋白的膜运动方面的作用一致，这对于诸如神经突生长和突触修饰等高动态过程可能很重要。
