Stanga Serena, Zanou Nadège, Audouard Emilie, Tasiaux Bernadette, Contino Sabrina, Vandermeulen Gaëlle, René Frédérique, Loeffler Jean-Philippe, Clotman Frédéric, Gailly Philippe, Dewachter Ilse, Octave Jean-Noël, Kienlen-Campard Pascal
Alzheimer Research Group, Institute of Neuroscience, Université Catholique de Louvain, Brussels, Belgium;
Laboratory of Cell Physiology, Institute of Neuroscience, Université Catholique de Louvain, Brussels, Belgium;
FASEB J. 2016 May;30(5):1696-711. doi: 10.1096/fj.15-278739. Epub 2015 Dec 30.
Besides its crucial role in the pathogenesis of Alzheimer's disease, the knowledge of amyloid precursor protein (APP) physiologic functions remains surprisingly scarce. Here, we show that APP regulates the transcription of the glial cell line-derived neurotrophic factor (GDNF). APP-dependent regulation of GDNF expression affects muscle strength, muscular trophy, and both neuronal and muscular differentiation fundamental for neuromuscular junction (NMJ) maturation in vivo In a nerve-muscle coculture model set up to modelize NMJ formation in vitro, silencing of muscular APP induces a 30% decrease in secreted GDNF levels and a 40% decrease in the total number of NMJs together with a significant reduction in the density of acetylcholine vesicles at the presynaptic site and in neuronal maturation. These defects are rescued by GDNF expression in muscle cells in the conditions where muscular APP has been previously silenced. Expression of GDNF in muscles of amyloid precursor protein null mice corrected the aberrant synaptic morphology of NMJs. Our findings highlight for the first time that APP-dependent GDNF expression drives the process of NMJ formation, providing new insights into the link between APP gene regulatory network and physiologic functions.-Stanga, S., Zanou, N., Audouard, E., Tasiaux, B., Contino, S., Vandermeulen, G., René, F., Loeffler, J.-P., Clotman, F., Gailly, P., Dewachter, I., Octave, J.-N., Kienlen-Campard, P. APP-dependent glial cell line-derived neurotrophic factor gene expression drives neuromuscular junction formation.
除了在阿尔茨海默病发病机制中起关键作用外，关于淀粉样前体蛋白（APP）生理功能的了解仍然非常有限。在此，我们表明APP可调节胶质细胞源性神经营养因子（GDNF）的转录。APP对GDNF表达的依赖性调节会影响肌肉力量、肌肉发育，以及体内神经肌肉接头（NMJ）成熟所必需的神经元和肌肉分化。在用于模拟体外NMJ形成的神经-肌肉共培养模型中，沉默肌肉中的APP会导致分泌的GDNF水平降低30%，NMJ总数减少40%，同时突触前位点乙酰胆碱囊泡密度和神经元成熟度显著降低。在先前已沉默肌肉APP的条件下，肌肉细胞中GDNF的表达可挽救这些缺陷。在淀粉样前体蛋白基因敲除小鼠的肌肉中表达GDNF可纠正NMJ异常的突触形态。我们的研究结果首次表明，APP依赖性GDNF表达驱动NMJ形成过程，为APP基因调控网络与生理功能之间的联系提供了新的见解。-斯坦加，S.，扎努，N.，奥杜阿尔德，E.，塔肖，B.，孔蒂诺，S.，范德默伦，G.，勒内，F.，勒夫勒，J.-P.，克洛特曼，F.，盖利，P.，德瓦赫特，I.，奥克塔夫，J.-N.，基恩伦-坎帕尔，P. APP依赖性胶质细胞源性神经营养因子基因表达驱动神经肌肉接头形成。
