التفاصيل البيبلوغرافية
| العنوان: |
Altered amyloid-β structure markedly reduces gliosis in the brain of mice harboring the Uppsala APP deletion |
| المؤلفون: |
Pagnon de la Vega, María, Syvänen, Stina, Giedraitis, Vilmantas, Hooley, Monique, Konstantinidis, Evangelos, Meier, Silvio R., Rokka, Johanna, Eriksson, Jonas, Aguilar, Ximena, Spires-Jones, Tara L., Lannfelt, Lars, Nilsson, Lars N. G., Erlandsson, Anna, Hultqvist, Greta, Ingelsson, Martin, Sehlin, Dag |
| المساهمون: |
Vetenskapsrådet, Alzheimerfonden, Hjärnfonden, Torsten Söderbergs Stiftelse, Åhlén-stiftelsen, Magnus Bergvalls Stiftelse, Stiftelsen för Gamla Tjänarinnor, Gun och Bertil Stohnes Stiftelse, Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse, Stiftelsen Sigurd and Elsa Goljes Minne, Uppsala University |
| المصدر: |
Acta Neuropathologica Communications ; volume 12, issue 1 ; ISSN 2051-5960 |
| بيانات النشر: |
Springer Science and Business Media LLC |
| سنة النشر: |
2024 |
| مصطلحات موضوعية: |
Cellular and Molecular Neuroscience, Neurology (clinical), Pathology and Forensic Medicine |
| الوصف: |
Deposition of amyloid beta (Aβ) into plaques is a major hallmark of Alzheimer’s disease (AD). Different amyloid precursor protein ( APP ) mutations cause early-onset AD by altering the production or aggregation properties of Aβ. We recently identified the Uppsala APP mutation ( APPUpp ), which causes Aβ pathology by a triple mechanism: increased β-secretase and altered α-secretase APP cleavage, leading to increased formation of a unique Aβ conformer that rapidly aggregates and deposits in the brain. The aim of this study was to further explore the effects of APPUpp in a transgenic mouse model (tg-UppSwe), expressing human APP with the APPUpp mutation together with the APPSwe mutation. Aβ pathology was studied in tg-UppSwe brains at different ages, using ELISA and immunohistochemistry. In vivo PET imaging with three different PET radioligands was conducted in aged tg-UppSwe mice and two other mouse models; tg-ArcSwe and tg-Swe. Finally, glial responses to Aβ pathology were studied in cell culture models and mouse brain tissue, using ELISA and immunohistochemistry. Tg-UppSwe mice displayed increased β-secretase cleavage and suppressed α-secretase cleavage, resulting in AβUpp42 dominated diffuse plaque pathology appearing from the age of 5–6 months. The γ-secretase cleavage was not affected. Contrary to tg-ArcSwe and tg-Swe mice, tg-UppSwe mice were [ 11 C]PiB-PET negative. Antibody-based PET with the 3D6 ligand visualized Aβ pathology in all models, whereas the Aβ protofibril selective mAb158 ligand did not give any signals in tg-UppSwe mice. Moreover, unlike the other two models, tg-UppSwe mice displayed a very faint glial response to the Aβ pathology. The tg-UppSwe mouse model thus recapitulates several pathological features of the Uppsala APP mutation carriers. The presumed unique structural features of AβUpp42 aggregates were found to affect their interaction with anti-Aβ antibodies and profoundly modify the Aβ-mediated glial response, which may be important aspects to consider for further development ... |
| نوع الوثيقة: |
article in journal/newspaper |
| اللغة: |
English |
| DOI: |
10.1186/s40478-024-01734-x |
| DOI: |
10.1186/s40478-024-01734-x.pdf |
| DOI: |
10.1186/s40478-024-01734-x/fulltext.html |
| الإتاحة: |
https://doi.org/10.1186/s40478-024-01734-xTest |
| حقوق: |
https://creativecommons.org/licenses/by/4.0Test ; https://creativecommons.org/licenses/by/4.0Test |
| رقم الانضمام: |
edsbas.BA01CFDD |
| قاعدة البيانات: |
BASE |
