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APP interacts with LRP4 and agrin to coordinate the development of the neuromuscular junction in mice

Hong Y Choi1, Yun Liu, Christian Tennert

  • 1Department of Molecular Genetics , University of Texas Southwestern Medical Center , Dallas , United States.

Elife
|August 30, 2013
PubMed

Insights

Amyloid precursor protein (APP) interacts with LRP4 and agrin to regulate neuromuscular junction formation. Genetic defects in APP and LRP4 lead to severe NMJ defects and perinatal lethality in mice.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Genetics

Background:

  • Alzheimer's disease involves Apolipoprotein E (ApoE), its receptors, and Amyloid Precursor Protein (APP).
  • The ApoE receptor LRP4 and APP are crucial for neuromuscular junction (NMJ) formation and function.

Purpose of the Study:

  • To investigate the interaction between APP, LRP4, and agrin in NMJ formation.
  • To elucidate the molecular mechanisms by which APP regulates NMJ development.

Main Methods:

  • In vitro studies using cultured myotubes.
  • Genetic analysis in mice with targeted deletions of APP and LRP4.

Main Results:

  • APP directly interacts with LRP4, a co-receptor for muscle-specific tyrosine kinase (MuSK).
  • Agrin, an LRP4 ligand, enhances APP-LRP4 interaction and APP's role in acetylcholine receptor (AChR) clustering.
  • Combined deletion of APP and LRP4 leads to severe NMJ defects, growth retardation, and perinatal lethality.

Conclusions:

  • APP plays a novel role in neuromuscular synapse formation via hetero-oligomeric interactions with LRP4 and agrin.
  • These findings offer new insights into the molecular basis of NMJ formation and maintenance.
Keywords:
Alzheimer's diseaseApoELRPMousenervous system developmentneurodegenerationneuromuscular synapse

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