APP-dependent regulation of GDNF expression controls neuromuscular junctions formation

Besides its crucial role in the pathogenesis of Alzheimer's disease (AD), our knowledge of the physiological function of the Amyloid Precursor Protein (APP) remains surprisingly scarce. We found that APP regulates the transcription of the Glial cell line-Derived Neutrophic Factor (GDNF). APP null mice (APP-/-) showed impaired force at grip strength tests and at mechanic measurements on isolated muscles, together with muscular atrophy and defective neuromuscular junctions (NMJs). APP and GDNF expression levels increase during differentiation and myoblasts fusion of skeletal muscle cells. Their overexpression or silencing respectively favors or impairs muscular differentiation. A co-culture model of muscle cells and cholinergic neurons was set up to generate NMJs in vitro. Silencing of muscular APP induced a significant decrease in secreted GDNF levels, in the total number of NMJs, in the localization and density of acetylcholine vesicles and in neuronal maturation. These defects were rescued by GDNF expression in muscle cells. Our findings highlight that APP-dependent GDNF expression is implicated in the process of neuronal and muscular differentiation involved in NMJs formation