Objective Death receptor 6 (DR6) is a death domain-containing receptor of the TNFR superfamily with an apparent regulatory function in hematopoietic and neuronal cells.Overexpression of DR6 in some cell lines leads to apoptosis and the activation of stress kinases.Recently, the extracellular fragment of β-amyloid precursor protein (N-APP) protein was reported to function as a DR6 ligand and to trigger DR6-dependent death of neurons and neurites degeneration.However, it is not clear whether amyloid-induced cell damage correlated with N-APP and DR6.In this study we investigate whether N-APP affects Aβ-induced neurotoxicity through DR6.Methods The cell effect of APP17-286 was measured by MTT and LDH assay.The expression of DR6, Bax/Bcl-2 and cleaved-caspase 3 and 6 activation after Aβ and APP17-286 treatment was identified by western blot or immunochemistry.Results (1) Aβ induced increased expression of DR6.APP17-286 enhanced Aβ-induced cell injury.(2)APP17-286 protein strengthened Aβ-induced cytotoxicity through activation of apoptosis pathway, including increased cleaved caspase-3 or 6 and increase the ratio of Bax/Bcl-2.However, it was not observed that the activated caspase-3 was uniquely distributed in neuritis.(3)The DR6 antibody pretreatment could inhibit the effects of Aβ and APP17-286 on apoptosis pathway.Conclusion APP17-286 could deteriorate Aβ-induced cytotoxicity.