When overexpressed, a short cytoplasmic domain of the amyloid precursor protein (APP), normally unmasked in the brain of Alzheimer's disease patients, activates caspase-3 and induces neuronal death. Death induction by this "Jcasp" domain is lost when tyrosine 653 is changed into an aspartate, suggesting specific interactions with unknown partners. To identify these putative partners and start to elucidate the mechanisms involved in Jcasp-induced cell death, we internalized a biotinylated version of the peptide into primary neurons and analyzed intracellular interacting proteins by pull-down and mass spectrometry. We find that SET protein, also called template-activating factor (TAF1beta) or phosphatase 2A inhibitor 2 (I2(PP2A)), specifically binds Jcasp early after internalization and that SET and Jcasp interact directly in vitro. Down-regulation of SET reduces Jcasp-induced cell death, confirming a role of this protein in Jcasp-induced apoptosis. Conversely, SET gain of function increases cell death, which suggests that SET level is crucial for neuronal survival/death. Taken together, these results suggest that SET is part of a neuronal apoptotic pathway related to Alzheimer's disease and provides a new entry in the analysis of this pathology.