dc.contributor.author | Pagnon de la Vega, María | |
dc.contributor.author | Syvänen, Stina | |
dc.contributor.author | Giedraitis, Vilmantas | |
dc.contributor.author | Hooley, Monique | |
dc.contributor.author | Konstantinidis, Evangelos | |
dc.contributor.author | Meier, Silvio R. | |
dc.contributor.author | Rokka, Johanna | |
dc.contributor.author | Eriksson, Jonas | |
dc.contributor.author | Aguilar, Ximena | |
dc.contributor.author | Spires-Jones, Tara L. | |
dc.contributor.author | Lannfelt, Lars | |
dc.contributor.author | Nilsson, Lars N. G. | |
dc.contributor.author | Erlandsson, Anna | |
dc.contributor.author | Hultqvist, Greta | |
dc.contributor.author | Ingelsson, Martin | |
dc.contributor.author | Sehlin, Dag | |
dc.date.accessioned | 2024-02-06T06:02:44Z | |
dc.date.available | 2024-02-06T06:02:44Z | |
dc.date.issued | 2024 | |
dc.identifier.citation | Acta Neuropathologica Communications. 2024 Feb 05;12(1):22 | |
dc.identifier.uri | http://hdl.handle.net/10852/107580 | |
dc.description.abstract | 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. | |
dc.language.iso | eng | |
dc.rights | The Author(s); licensee BioMed Central Ltd. | |
dc.rights | Attribution 4.0 International | |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | |
dc.title | Altered amyloid-β structure markedly reduces gliosis in the brain of mice harboring the Uppsala APP deletion | |
dc.type | Journal article | |
dc.date.updated | 2024-02-06T06:02:45Z | |
dc.creator.author | Pagnon de la Vega, María | |
dc.creator.author | Syvänen, Stina | |
dc.creator.author | Giedraitis, Vilmantas | |
dc.creator.author | Hooley, Monique | |
dc.creator.author | Konstantinidis, Evangelos | |
dc.creator.author | Meier, Silvio R. | |
dc.creator.author | Rokka, Johanna | |
dc.creator.author | Eriksson, Jonas | |
dc.creator.author | Aguilar, Ximena | |
dc.creator.author | Spires-Jones, Tara L. | |
dc.creator.author | Lannfelt, Lars | |
dc.creator.author | Nilsson, Lars N. G. | |
dc.creator.author | Erlandsson, Anna | |
dc.creator.author | Hultqvist, Greta | |
dc.creator.author | Ingelsson, Martin | |
dc.creator.author | Sehlin, Dag | |
dc.identifier.doi | https://doi.org/10.1186/s40478-024-01734-x | |
dc.type.document | Tidsskriftartikkel | |
dc.type.peerreviewed | Peer reviewed | |
dc.type.version | PublishedVersion | |
cristin.articleid | 22 | |