Amyloid Precursor Protein regulation of GDNF expression controls neuromuscular junctions’ formation

Amyloid precursor protein (APP) plays a crucial role in Alzheimer's disease (AD) pathogenesis since its proteolytical cleavage generates β-amyloid peptide (Aβ). Here we show that APP regulates the transcription of the glial cell line-derived neutrophic factor (GDNF) in APP knock-out (APP-/-) cell lines and in APP null mice. This regulation plays a key role in the process of neuromuscular junctions’ (NMJs) formation. GDNF is a muscle-derived factor fundamental for the building of NMJs from where it can be retrogradely transported to neurons’ cell bodies. Monitoring myoblasts fusion in skeletal muscle cells (C2C12) we observed that GDNF and APP expression levels increase all along muscular differentiation, while respectively their overexpression or silencing favors or affects the process. In a co-culture model of C2C12 cells and cholinergic neurons to generate NMJs in vitro, silencing of APP in muscles caused a significant decrease in the number of NMJs compared to wild-type. This defect was restored by GDNF. Altogether, our findings highlight that APP-dependent GDNF expression has a critical involvement in neuronal and muscular differentiation implied in NMJs formation.