It has been previously reported that an Asp421 cleaved form of tau is toxic when expressed in cells. The purpose of this study was to understand if, and in what manner, the presence of Asp421 cleaved tau in neurons, which is generated by caspase cleavage, might facilitate neuronal death in Alzheimer's disease (AD). For these studies we used immortalized cortical neurons that inducibly express either a full-length tau isoform (T4) or an isoform that has been pseudo-truncated at Asp421 (T4C3), to mimic caspase-3 cleavage. Neurons expressing either T4 or T4C3 were treated with thapsigargin, a drug, which has been shown to induce endoplasmic reticulum (ER) stress. Following long-term treatment with thapsigargin, cells expressing T4C3 presented with a marked increase in cell toxicity, underscored by differential activation of caspase-3 in comparison with cells expressing T4. Furthermore, we found that an inhibitor of the ERK1/2 signaling pathway, which is upregulated to different extents in each cell type, significantly reduced toxicity in both T4 and T4C3 cells. Our results suggest that the presence of Asp421 cleaved tau may sensitize neurons to ER stressors and possibly potentiate cell death processes during AD progression.