Mutations in the β-amyloid precursor protein (APP) gene cause familial Alzheimer's disease (AD). Although amyloid β peptide (Aβ) is the principal constituent of senile plaques in AD, other cleavage products of APP are also implicated in playing a role in the pathogenesis of AD. C-terminal fragments of APP (APP-CTs), that contain complete Aβ sequence, are found in neuritic plaques, neurofibrillary tangles and the cytosol of lymphoblastoid cells obtained from AD patients. Our previous report demonstrated that APP-CT105 causes death of differentiated PC12 cells and cultured rat cortical neurons (Kim and Suh [1996] J. Neurochem. 67: 1172–1182) and induces strong inward currents in Xenopus oocyte (Fraser et al.,[1996] J. Neurochem. 66: 2034–2040). In the present study, to investigate which domain of APP-CT105 is responsible for the neurotoxicity, we have made deletion mutants of APP-CT105 without Aβ and transmembrane domain (TM) or without NPTY domain, a putative endocytosis signaling sequence, using the PCR-amplified strategy and the recombinant GST-fusion protein strategy. The effect on cell survival of the deletion mutants of APP-CT105 (8 μM) was then determined by the LDH and MTT assay. We found that C-terminal fragment without NPTY significantly causes cell death in NGF-differentiated PC12 cells and cultured rat cortical neurons. This finding suggests that NPTY may not play an important role in APP-CT105 mediated neurotoxicity. We found, however, that C-terminal fragment without Aβ and TM significantly induces neuronal cell death. Our results suggest that in addition to Aβ, C-terminal fragment of APP without Aβ and TM domain itself may also participate in the neuronal degeneration in AD. J. Neurosci. Res. 60: 565–570, 2000© 2000 Wiley-Liss, Inc.