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

Aims Alzheimer's disease (AD) is characterised by amyloid-beta (A beta) aggregates in the brain. Targeting A beta 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 A beta multimers. The enzyme tissue transglutaminase (TG2) is abundantly expressed in the human brain and plays a key role in post-translational modifications in A beta resulting in covalently cross-linked, stable and neurotoxic A beta 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 A beta-related pathology. Methods Here, we compared the effects on A beta 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 A beta 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 A beta(1-40), A beta(1-42) and/or A beta(40/42) 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 A beta deposits and the presence of reactive astrocytes associated with A beta deposits were analysed. Conclusions We found that absence of TG2 reduces the formation of A beta pathology in the APP23 mouse model, suggesting that TG2 may be a suitable therapeutic target for reducing A beta deposition in AD.