Alzheimer's disease (AD) is the most common cause of dementia. At the pre-symptomatic phase of the disease, the processing of the amyloid precursor protein (APP) produces toxic peptides, called amyloid-β 1–42 (Aβ 1–42). The downstream effects of Aβ 1–42 production are not completely uncovered. Here, we report the involvement of transglutaminase 1 (TG1) in in vitro AD models of neuronal toxicity. TG1 was increased at late stages of the disease in the hippocampus of a mouse model of AD and in primary cortical neurons undergoing stress. Silencing of TGM1 gene was sufficient to prevent Aβ-mediated neuronal death. Conversely, its overexpression enhanced cell death. TGM1 upregulation was mediated at the transcriptional level by an activator protein 1 (AP1) binding site that when mutated halted TGM1 promoter activation. These results indicate that TG1 acts downstream of Aβ-toxicity, and that its stress-dependent increase makes it suitable for pharmacological intervention.