Amyloid precursor protein and presenilin1 interact with the adaptor GRB2 and modulate ERK1,2 signaling

The amyloid precursor protein (APP) and the presenilins 1and 2 are genetically linked to the development of familialAlzheimer disease. APP is a single-pass transmembrane proteinand precursor of fibrillar and toxic amyloid- peptides, which areconsidered responsible for Alzheimer disease neurodegeneration.Presenilins are multipass membrane proteins, involved inthe enzymatic cleavage of APP and other signaling receptorsand transducers. The role of APP and presenilins in Alzheimerdisease development seems to be related to the formation ofamyloid- peptides; however, their physiological function, reciprocal interaction, and molecular mechanisms leading toneurodegeneration are unclear. APP and presenilins are alsoinvolved in multiple interactions with intracellular proteins, thesignificance of which is under investigation. Among the differentAPP-interacting proteins, we focused our interest on theGRB2 adaptor protein, which connects cell surface receptors tointracellular signaling pathways. In this study we provide evidenceby co-immunoprecipitation experiments, confocal andelectron microscopy, and by fluorescence resonance energytransfer experiments that both APP and presenilin1 interactwith GRB2 in vesicular structures at the centrosome of the cell.The final target for these interactions is ERK1,2, which is activatedin mitotic centrosomes in a PS1- and APP-dependentmanner. These data suggest that both APP and presenilin1 canbe part of a common signaling pathway that regulates ERK1,2and the cell cycle.