APP interacts with LRP4 and Agrin to coordinate the development of the neuromuscular junction in mice
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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.
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At the neuromuscular junction, Lrp4, APP, and MuSK form a complex that prepatterns the muscle.
“at the NMJ, Lrp4, APP and muscle-specific kinase (MuSK) form a complex to prepattern the muscle [88–90]”
From ApoE, ApoE Receptors, and the Synapse in Alzheimer's Disease (2017) · cites this paper as [88]
Agrin released from motor neurons signals through APP, MuSK, and Lrp4 to recruit nicotinic acetylcholine receptors.
“Agrin is released from the motor neuron and signals through APP, MuSK and Lrp4 to recruit nicotinic acetylcholine receptors (AChRs).”
From ApoE, ApoE Receptors, and the Synapse in Alzheimer's Disease (2017) · cites this paper as [88]
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- Authors
- Choi, H. Y., Liu, Y., Tennert, C., Sugiura, Y., Karakatsani, A., Kröger, S., Johnson, E. B., Hammer, R. E., Lin, W., & Herz, J.
- Affiliations
- Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, United States
- The University of Texas Southwestern Medical Center (US)
- Ludwig-Maximilians-Universität München (DE)
- University of Freiburg (DE)
- Corresponding author
- Lin, Weichun
- Herz, Joachim
- Venue
- eLife
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2013-08-20
- Volume
- 2
- Pages
- e00220-e00220
- ISSN
- 2050-084X (ISSN-L)
- PMC
- PMC3748711
- OpenAlex
- W2036930909
- Cited by
- 71
- References
- 72
- Citations by year
- 2026: 4 · 2025: 4 · 2024: 2 · 2023: 8 · 2022: 3 · 2021: 7 · 2020: 7 · 2019: 6 · 2018: 4 · 2017: 10 · 2016: 2 · 2015: 8 · 2014: 6
- FWCI
- 2.39
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- eLife (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institutes of Health (HL20948, HL63762, NS055028)
- American Health Assistance Foundation
- Lupe Murchison Foundation
- Consortium for Frontotemporal Dementia Research
- Deutsche Forschungsgemeinschaft (SFB780)
- Alexander von Humboldt Stiftung
- Brightfocus Foundation
- Alzheimer’s Disease Center
- Cain Foundation in Medical Research
- Alexander von Humboldt-Stiftung
- Cain Foundation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Keywords
- amyloid precursor protein, LRP4, agrin, neuromuscular junction formation, acetylcholine receptor clustering, musk, synaptic development, perinatal lethality, myotubes
- MeSH terms
- Alzheimer Disease, Animals, Humans, Ligands, Mice, Inbred C57BL, Neuromuscular Junction, Phosphorylation, Protein Binding, Receptors, Cholinergic, Receptors, LDL, Transfection, Signal Transduction, Amyloid beta-Protein Precursor, Agrin, Mice, Knockout, Muscle Fibers, Skeletal, Receptor Protein-Tyrosine Kinases, LDL-Receptor Related Proteins, Multiprotein Complexes, Protein Interaction Domains and Motifs, Mice, 129 Strain, HEK293 Cells
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