Amyloid precursor protein interacts with notch receptors

Area of Science:

• Neuroscience
• Molecular Biology
• Cell Biology

Background:

• The amyloid precursor protein (APP) is conserved across species and is known as the precursor to neurotoxic Abeta peptides implicated in Alzheimer's disease.
• While APP's role in Alzheimer's is established, its broader functions and interactions remain incompletely understood.
• Investigating APP's molecular interactions can elucidate its pleiotropic effects and cellular roles.

Purpose of the Study:

• To identify novel protein interactors of the plasma membrane isoform of APP.
• To explore potential new functions of APP beyond its role in Alzheimer's disease.
• To understand the molecular basis of APP's diverse cellular effects.

Main Methods:

• Utilized a membrane-impermeable crosslinker to capture proteins binding to transmembrane APP in HEK293 cells and primary neurons.
• Employed mass spectrometry to identify APP-interacting proteins from immunopurified complexes.
• Confirmed interactions using immunoprecipitation studies and visualized protein colocalization via cotransfection and fluorescent tagging.

Main Results:

• Notch2 was identified as a potential binding partner of APP through mass spectrometry analysis of neuronal APP complexes.
• Immunoprecipitation studies confirmed the interaction between APP and Notch2 in mammalian cells.
• Notch1 also coimmunoprecipitated with APP, indicating potential cross-talk between APP and Notch family members.
• APP and Notch2 were observed to colocalize on the plasma membrane, with some intracellular colocalization and distinct localization patterns.

Conclusions:

• APP interacts with members of the Notch family, specifically Notch1 and Notch2.
• These interactions suggest a role for APP in modulating cell function through cross-talk with the Notch signaling pathway.
• The identification of APP-interacting proteins like Notch receptors provides insights into previously unrecognized functions of APP.