The amyloid precursor protein is a conserved Wnt receptor

Area of Science:

• Neuroscience
• Molecular Biology
• Cell Biology

Background:

• Amyloid Precursor Protein (APP) is essential for neuronal development and activity, but its precise molecular function and potential roles as a receptor remain unclear.
• Identifying APP's ligands and understanding how they modulate its function are critical for deciphering its role in neuronal processes.

Purpose of the Study:

• To investigate whether APP functions as a receptor and identify its potential ligands.
• To elucidate the molecular mechanisms by which Wnt ligands affect APP protein levels, trafficking, and neuronal development.

Main Methods:

• APP binding assays with Wnt ligands (Wnt3a and Wnt5a).
• Analysis of full-length APP (flAPP) recycling, stability, and lysosomal targeting.
• CRISPR-Cas9 mediated deletion of the APP Cysteine-Rich Domain (CRD).
• Assessment of axonal and dendritic growth in primary cortical neurons from APP-deficient mice.

Main Results:

• APP directly binds to Wnt3a and Wnt5a.
• Wnt3a binding enhances flAPP recycling and stability, while Wnt5a promotes lysosomal degradation, reducing flAPP levels.
• The CRD of APP is essential for Wnt binding and subsequent modulation of flAPP levels and trafficking.
• Loss of APP in primary cortical neurons leads to increased axonal and reduced dendritic growth, a phenotype rescued by full-length APP in a CRD-dependent manner.

Conclusions:

• APP acts as a receptor for Wnt ligands Wnt3a and Wnt5a, with binding differentially regulating APP protein levels and trafficking.
• The CRD of APP is a critical mediator of Wnt interactions, influencing APP stability and neuronal morphology.
• Wnt signaling, through APP, plays a significant role in regulating neuronal development, specifically axonal and dendritic growth.