Absence of tissue transglutaminase reduces amyloid-beta pathology in APP23 mice

Micha M. M. Wilhelmus*, Osoul Chouchane, Maarten Loos, Cornelis A. M. Jongenelen, John J. P. Brevé, Allert Jonker, John G. J. M. Bol, August B. Smit, Benjamin Drukarch

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


Aims: Alzheimer's disease (AD) is characterised by amyloid-beta (Aβ) aggregates in the brain. Targeting Aβ aggregates is a major approach for AD therapies, although attempts have had little to no success so far. A novel treatment option is to focus on blocking the actual formation of Aβ multimers. The enzyme tissue transglutaminase (TG2) is abundantly expressed in the human brain and plays a key role in post-translational modifications in Aβ resulting in covalently cross-linked, stable and neurotoxic Aβ oligomers. In vivo absence of TG2 in the APP23 mouse model may provide evidence that TG2 plays a key role in development and/or progression of Aβ-related pathology. Methods: Here, we compared the effects on Aβ pathology in the presence or absence of TG2 using 12-month-old wild type, APP23 and a crossbreed of the TG2−/− mouse model and APP23 mice (APP23/TG2−/−). Results: Using immunohistochemistry, we found that the number of Aβ deposits was significantly reduced in the absence of TG2 compared with age-matched APP23 mice. To pinpoint possible TG2-associated mechanisms involved in this observation, we analysed soluble brain Aβ1–40, Aβ1–42 and/or Aβ40/42 ratio, and mRNA levels of human APP and TG2 family members present in brain of the various mouse models. In addition, using immunohistochemistry, both beta-pleated sheet formation in Aβ deposits and the presence of reactive astrocytes associated with Aβ deposits were analysed. Conclusions: We found that absence of TG2 reduces the formation of Aβ pathology in the APP23 mouse model, suggesting that TG2 may be a suitable therapeutic target for reducing Aβ deposition in AD.
Original languageEnglish
Article numbere12796
JournalNeuropathology and Applied Neurobiology
Issue number4
Early online date2022
Publication statusPublished - Jun 2022

Cite this