Altered amyloid-β structure markedly reduces gliosis in the brain of mice harboring the Uppsala APP deletion
| العنوان: | Altered amyloid-β structure markedly reduces gliosis in the brain of mice harboring the Uppsala APP deletion |
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| المؤلفون: | Pagnon de la Vega, María, Syvänen, Stina, Giedraitis, Vilmantas, Hooley, Monique, Konstantinidis, Evangelos, 1990, Meier, Silvio R., Rokka, Johanna, Eriksson, Jonas, Aguilar, Ximena, Spires-Jones, Tara L., Lannfelt, Lars, Nilsson, Lars N. G., Erlandsson, Anna, Hultqvist, Greta, 1980, Ingelsson, Martin, Sehlin, Dag, 1976 |
| المصدر: | Acta neuropathologica communications. 12(1) |
| مصطلحات موضوعية: | Alzheimer's disease (AD), Amyloid precursor protein (APP), Amyloid-beta (A beta), PET imaging, Microglia, Astrocytes, Immunotherapy |
| 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 [11C]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 of AD therapies. |
| وصف الملف: | electronic |
| الوصول الحر: | https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-523728Test https://doi.org/10.1186/s40478-024-01734-xTest https://uu.diva-portal.org/smash/get/diva2:1840756/FULLTEXT01.pdfTest |
| قاعدة البيانات: | SwePub |
| DOI: | 10.1186/s40478-024-01734-x |
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