Increased transcription of transglutaminase 1 mediates neuronal death in in vitro models of neuronal stress and Aβ1–42-mediated toxicity

Debasmita Tripathy, Alice Migazzi, Federica Costa, Alessandro Roncador, Pamela Gatto, Federica Fusco, Lucia Boeri, Diego Albani, J. Leon Juárez-Hernández, Carlo Musio, Laura Colombo, Mario Salmona, M. M.Micha Wilhelmus, Benjamin Drukarch, Maria Pennuto, Manuela Basso*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

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.

Original languageEnglish
Article number104849
JournalNeurobiology of Disease
Volume140
DOIs
Publication statusPublished - Jul 2020

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