title: APP-dependent glial cell line-derived neurotrophic factor gene expression drives neuromuscular junction formation.
abstract: 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.
authors.affiliation: Alzheimer Research Group, Institute of Neuroscience, Université Catholique de Louvain, Brussels, Belgium;
authors.forename: Serena
authors.initials: S
authors.lastname: Stanga
authors.affiliation: Laboratory of Cell Physiology, Institute of Neuroscience, Université Catholique de Louvain, Brussels, Belgium;
authors.forename: Nadège
authors.initials: N
authors.lastname: Zanou
authors.affiliation: Laboratory of Neural Differentiation, Institute of Neuroscience, Université Catholique de Louvain, Brussels, Belgium;
authors.forename: Emilie
authors.initials: E
authors.lastname: Audouard
authors.affiliation: Alzheimer Research Group, Institute of Neuroscience, Université Catholique de Louvain, Brussels, Belgium;
authors.forename: Bernadette
authors.initials: B
authors.lastname: Tasiaux
authors.affiliation: Alzheimer Research Group, Institute of Neuroscience, Université Catholique de Louvain, Brussels, Belgium;
authors.forename: Sabrina
authors.initials: S
authors.lastname: Contino
authors.affiliation: Advanced Drug Delivery and Biomaterials, Louvain Drug Research Institute, Université Catholique de Louvain, Brussels, Belgium; and.
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Vandermeulen
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité 1118 Mécanismes Centraux et Périphériques de la Neurodégénérescence, Université de Strasbourg, Strasbourg Cedex, France.
authors.forename: Frédérique
authors.initials: F
authors.lastname: René
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité 1118 Mécanismes Centraux et Périphériques de la Neurodégénérescence, Université de Strasbourg, Strasbourg Cedex, France.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Loeffler
authors.affiliation: Laboratory of Neural Differentiation, Institute of Neuroscience, Université Catholique de Louvain, Brussels, Belgium;
authors.forename: Frédéric
authors.initials: F
authors.lastname: Clotman
authors.affiliation: Laboratory of Cell Physiology, Institute of Neuroscience, Université Catholique de Louvain, Brussels, Belgium;
authors.forename: Philippe
authors.initials: P
authors.lastname: Gailly
authors.affiliation: Alzheimer Research Group, Institute of Neuroscience, Université Catholique de Louvain, Brussels, Belgium;
authors.forename: Ilse
authors.initials: I
authors.lastname: Dewachter
authors.affiliation: Alzheimer Research Group, Institute of Neuroscience, Université Catholique de Louvain, Brussels, Belgium;
authors.forename: Jean-Noël
authors.initials: JN
authors.lastname: Octave
authors.affiliation: Alzheimer Research Group, Institute of Neuroscience, Université Catholique de Louvain, Brussels, Belgium; pascal.kienlen-campard@uclouvain.be.
authors.forename: Pascal
authors.initials: P
authors.lastname: Kienlen-Campard
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D005347:Fibroblasts / Q000502:physiology*; D005786:Gene Expression Regulation / Q000502:physiology*; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000502:physiology; D009469:Neuromuscular Junction / Q000502:physiology*
chemical_list: D016564:Amyloid beta-Protein Precursor; D051100:Glial Cell Line-Derived Neurotrophic Factor
keywords: APP knockout mice; Alzheimer’s disease; gene transcription; muscle electroporation; nerve–muscle coculture