title: APP interacts with LRP4 and agrin to coordinate the development of the neuromuscular junction in mice.
abstract: 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(-/-);LRP4(ECD/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. DOI:http://dx.doi.org/10.7554/eLife.00220.001.
authors.affiliation: Department of Molecular Genetics , University of Texas Southwestern Medical Center , Dallas , United States.
authors.forename: Hong Y
authors.initials: HY
authors.lastname: Choi
authors.forename: Yun
authors.initials: Y
authors.lastname: Liu
authors.forename: Christian
authors.initials: C
authors.lastname: Tennert
authors.forename: Yoshie
authors.initials: Y
authors.lastname: Sugiura
authors.forename: Andromachi
authors.initials: A
authors.lastname: Karakatsani
authors.forename: Stephan
authors.initials: S
authors.lastname: Kröger
authors.forename: Eric B
authors.initials: EB
authors.lastname: Johnson
authors.forename: Robert E
authors.initials: RE
authors.lastname: Hammer
authors.forename: Weichun
authors.initials: W
authors.lastname: Lin
authors.forename: Joachim
authors.initials: J
authors.lastname: Herz
mesh_terms: D018171:Agrin / Q000378:metabolism*; D000544:Alzheimer Disease / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D057809:HEK293 Cells; D006801:Humans; D026502:LDL-Receptor Related Proteins; D008024:Ligands; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046912:Multiprotein Complexes; D018485:Muscle Fibers, Skeletal / Q000378:metabolism*; D009469:Neuromuscular Junction / Q000254:growth & development / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D011950:Receptors, Cholinergic / Q000378:metabolism; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection
chemical_list: D018171:Agrin; D016564:Amyloid beta-Protein Precursor; D026502:LDL-Receptor Related Proteins; D008024:Ligands; C116415:Lrp4 protein, mouse; D046912:Multiprotein Complexes; D011950:Receptors, Cholinergic; D011973:Receptors, LDL; C511695:MuSK protein, mouse; D020794:Receptor Protein-Tyrosine Kinases
keywords: Alzheimer's disease; ApoE; LRP; Mouse; nervous system development; neurodegeneration; neuromuscular synapse