APP interacts with LRP4 and agrin to coordinate the development of the neuromuscular junction in mice
Hong Y Choi,
Yun Liu,
Christian Tennert,
Yoshie Sugiura,
Andromachi Karakatsani,
Stephan Kröger,
Eric B Johnson,
Robert E Hammer,
Weichun Lin,
Joachim Herz
Affiliations
Hong Y Choi
Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, United States
Yun Liu
Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, United States
Christian Tennert
Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, United States
Yoshie Sugiura
Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, United States
Andromachi Karakatsani
Department of Physiological Genomics, Ludwig-Maximilians-Universität München, München, Germany
Stephan Kröger
Department of Physiological Genomics, Ludwig-Maximilians-Universität München, München, Germany
Eric B Johnson
Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, United States
Robert E Hammer
Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, United States
Weichun Lin
Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, United States
Joachim Herz
Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, United States; Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, United States; Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, United States; Center for Neuroscience, Albert-Ludwigs-Universität Freiburg, Freiburg, Germany
ApoE, ApoE receptors and APP cooperate in the pathogenesis of Alzheimer’s disease. Intriguingly, the ApoE receptor LRP4 and APP are also required for normal formation and function of the neuromuscular junction (NMJ). In this study, we show that APP interacts with LRP4, an obligate co-receptor for muscle-specific tyrosine kinase (MuSK). Agrin, a ligand for LRP4, also binds to APP and co-operatively enhances the interaction of APP with LRP4. In cultured myotubes, APP synergistically increases agrin-induced acetylcholine receptor (AChR) clustering. Deletion of the transmembrane domain of LRP4 (LRP4 ECD) results in growth retardation of the NMJ, and these defects are markedly enhanced in APP−/−;LRP4ECD/ECD mice. Double mutant NMJs are significantly reduced in size and number, resulting in perinatal lethality. Our findings reveal novel roles for APP in regulating neuromuscular synapse formation through hetero-oligomeric interaction with LRP4 and agrin and thereby provide new insights into the molecular mechanisms that govern NMJ formation and maintenance.
