AMYLOID PRECURSOR PROTEIN REGULATION OF GDNF EXPRESSION CONTROLS NEUROMUSCULAR JUNCTIONS FORMATION
(2015) 12th International Conference on Alzheimer’s and Parkinson’s Diseases — Location: Nice, France (18.March.2015)
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- Objectives: Beside its crucial role in Alzheimer's disease (AD) pathogenesis, different functions have been attributed to the amyloid precursor protein (APP) but its pivotal role is difficult to depict. We found that APP regulates GDNF (Glial cell-line Derived Neurotrophic Factor) expression. Our work aims at investigating the role of APP-dependent GDNF expression in neuromuscular junctions. Methods: Following transcriptome analysis, qRT-PCR, ELISA and reporter gene assays were performed on APPKO mouse embryonic fibroblasts (APP -/- MEFs) stably re-expressing APP695 and APP751. APP and GDNF expression have been monitored throughout skeletal muscle differentiation (C2C12 cells) upon APP silencing (small interfering RNA) and/or GDNF plasmid expression. We performed grip strength tests, mechanic measurements on isolated muscles and immunohistochemistry (IHC) of neuromuscular junctions (NMJs) on APP -/- mice. A co-culture model of C2C12 and cholinergic neurons (NG108-15) was set up to analyze the effects of APP silencing or GDNF expression on NMJs formation and neuronal maturation by immunocytochemistry (ICC). Results: GDNF mRNA and protein levels together with GDNF transcriptional activity are down-regulated in APP -/- MEFs and restored specifically by APP751 isoform. GDNF and APP levels increase during muscular differentiation. Their overexpression or silencing favors or affects the process, respectively. APP-dependent GDNF expression controls the muscular phenotype and defective NMJs in APP -/- mice. In the co-culture model, GDNF restores the number of NMJs and neuronal maturation impaired by APP silencing. Conclusions: APP controls GDNF expression with a critical involvement in neuronal and muscular differentiation underlying NMJs formation.
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Stanga, S., & Kienlen-Campard, P. (2015). AMYLOID PRECURSOR PROTEIN REGULATION OF GDNF EXPRESSION CONTROLS NEUROMUSCULAR JUNCTIONS FORMATION. 12th International Conference on Alzheimer’s and Parkinson’s Diseases, Nice, France. https://hdl.handle.net/2078.5/185369