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Absence of tissue transglutaminase reduces amyloid‐beta pathology in APP23 mice
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 multime...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9304226/ https://www.ncbi.nlm.nih.gov/pubmed/35141929 http://dx.doi.org/10.1111/nan.12796 |
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author | Wilhelmus, Micha M. M. Chouchane, Osoul Loos, Maarten Jongenelen, Cornelis A. M. Brevé, John J. P. Jonker, Allert Bol, John G. J. M. Smit, August B. Drukarch, Benjamin |
author_facet | Wilhelmus, Micha M. M. Chouchane, Osoul Loos, Maarten Jongenelen, Cornelis A. M. Brevé, John J. P. Jonker, Allert Bol, John G. J. M. Smit, August B. Drukarch, Benjamin |
author_sort | Wilhelmus, Micha M. M. |
collection | PubMed |
description | 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 Aβ(1–40), Aβ(1–42) and/or Aβ(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 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. |
format | Online Article Text |
id | pubmed-9304226 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-93042262022-07-28 Absence of tissue transglutaminase reduces amyloid‐beta pathology in APP23 mice Wilhelmus, Micha M. M. Chouchane, Osoul Loos, Maarten Jongenelen, Cornelis A. M. Brevé, John J. P. Jonker, Allert Bol, John G. J. M. Smit, August B. Drukarch, Benjamin Neuropathol Appl Neurobiol Original Articles 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 Aβ(1–40), Aβ(1–42) and/or Aβ(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 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. John Wiley and Sons Inc. 2022-02-23 2022-06 /pmc/articles/PMC9304226/ /pubmed/35141929 http://dx.doi.org/10.1111/nan.12796 Text en © 2022 The Authors. Neuropathology and Applied Neurobiology published by John Wiley & Sons Ltd on behalf of British Neuropathological Society. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made. |
spellingShingle | Original Articles Wilhelmus, Micha M. M. Chouchane, Osoul Loos, Maarten Jongenelen, Cornelis A. M. Brevé, John J. P. Jonker, Allert Bol, John G. J. M. Smit, August B. Drukarch, Benjamin Absence of tissue transglutaminase reduces amyloid‐beta pathology in APP23 mice |
title | Absence of tissue transglutaminase reduces amyloid‐beta pathology in APP23 mice |
title_full | Absence of tissue transglutaminase reduces amyloid‐beta pathology in APP23 mice |
title_fullStr | Absence of tissue transglutaminase reduces amyloid‐beta pathology in APP23 mice |
title_full_unstemmed | Absence of tissue transglutaminase reduces amyloid‐beta pathology in APP23 mice |
title_short | Absence of tissue transglutaminase reduces amyloid‐beta pathology in APP23 mice |
title_sort | absence of tissue transglutaminase reduces amyloid‐beta pathology in app23 mice |
topic | Original Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9304226/ https://www.ncbi.nlm.nih.gov/pubmed/35141929 http://dx.doi.org/10.1111/nan.12796 |
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