Studying APP and PrPC potential interaction under the context of AD

Introduction: Cellular prion protein (PrPC) has been implicated in the pathophysiological mechanisms induced by β-amyloid oligomers (AβOs) in Alzheimer’s disease (AD). Several studies suggest that PrPC may function as a receptor for Aβ, activating an intracellular signaling pathway. Since PrPC has a GPI anchor, its transducer role should be mediated by another transmembrane protein. A relevant candidate is the amyloid precursor protein (APP), extensively studied in the context of AD, and whose interaction with PrPC has previously been suggested by interactome studies.

Objective: The aim of this study was to evaluate PrPC and APP interaction in differentiated CAD cells before and after exposure to β-amyloid oligomers (AβOs).

Methods: For this purpose, we used both bioinformatic tools (protein-protein docking) and experimental approaches (colocalization and co-immunoprecipitation).

Results: Docking analysis revealed 35 residues forming contact points between the two proteins. Notably, the APP-E2 domain showed 12 interacting residues with PrPC which displayed favorable energy values. In cells previously exposed to AβOs 1-40 or unexposed, colocalization analyses between PrPC and APP showed high Pearson correlation that was maintain after AβOs exposure.  Co-immunoprecipitation experiments under the same conditions demonstrated the interaction between the two proteins, despite the presence or absence of AβOs. Additionally, a 55 kDa APP fragment was detected, possibly corresponding to a previously described proteolyzed form.

Discussion: These findings provide preliminary evidence of an interaction between PrPC and APP and shows that this interaction is unaltered under an AD context.