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

Neuropathology and applied neurobiology 2022 Jun

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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. 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-/-). 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. 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. © 2022 The Authors. Neuropathology and Applied Neurobiology published by John Wiley & Sons Ltd on behalf of British Neuropathological Society.

Citation

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. Absence of tissue transglutaminase reduces amyloid-beta pathology in APP23 mice. Neuropathology and applied neurobiology. 2022 Jun;48(4):e12796