Amyloid beta-peptide (Abeta) plays a central role in the pathogenesis of Alzheimer's disease (AD). It is toxic to neurons, but the mechanism for its action remains largely unknown. Here, we have identified a novel death-inducing protein, Abeta-related DIP (AB-DIP), by two-hybrid screening of the human brain cDNA library and confirmed the binding of Abeta with AB-DIP by coimmunoprecipitation. Overexpression of AB-DIP-induced cell death and coexpression of Abeta enhanced the cell death. During apoptosis, the 97-kDa AB-DIP was cleaved to a 62-kDa protein (AB-DIP p62) at the caspase cleavage site, LEKD. It is more important that cotransfection of Abeta with AB-DIP produced the AB-DIP p62 fragment. Small interfering RNA-mediated knockdown of AB-DIP protein expression significantly protected neuroblastoma cells from Abeta-induced neurotoxicity. AB-DIP may mediate the neurotoxicity of Abeta, and therefore, AB-DIP may be a potential, therapeutic target for AD.