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Different amyloid precursor protein (<jats:italic>APP<\/jats:italic>) mutations cause early-onset AD by altering the production or aggregation properties of A\u03b2. We recently identified the <jats:italic>Uppsala APP<\/jats:italic> mutation (<jats:italic>APPUpp<\/jats:italic>), which causes A\u03b2 pathology by a triple mechanism: increased \u03b2-secretase and altered \u03b1-secretase APP cleavage, leading to increased formation of a unique A\u03b2 conformer that rapidly aggregates and deposits in the brain. The aim of this study was to further explore the effects of <jats:italic>APPUpp<\/jats:italic> in a transgenic mouse model (tg-UppSwe), expressing human <jats:italic>APP<\/jats:italic> with the <jats:italic>APPUpp<\/jats:italic> mutation together with the <jats:italic>APPSwe<\/jats:italic> mutation. A\u03b2 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 A\u03b2 pathology were studied in cell culture models and mouse brain tissue, using ELISA and immunohistochemistry. Tg-UppSwe mice displayed increased \u03b2-secretase cleavage and suppressed \u03b1-secretase cleavage, resulting in A\u03b2Upp42 dominated diffuse plaque pathology appearing from the age of 5\u20136\u00a0months. The \u03b3-secretase cleavage was not affected. Contrary to tg-ArcSwe and tg-Swe mice, tg-UppSwe mice were [<jats:sup>11<\/jats:sup>C]PiB-PET negative. Antibody-based PET with the 3D6 ligand visualized A\u03b2 pathology in all models, whereas the A\u03b2 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 A\u03b2 pathology. The tg-UppSwe mouse model thus recapitulates several pathological features of the <jats:italic>Uppsala APP<\/jats:italic> mutation carriers. The presumed unique structural features of A\u03b2Upp42 aggregates were found to affect their interaction with anti-A\u03b2 antibodies and profoundly modify the A\u03b2-mediated glial response, which may be important aspects to consider for further development of AD therapies.<\/jats:p>","DOI":"10.1186\/s40478-024-01734-x","type":"journal-article","created":{"date-parts":[[2024,2,5]],"date-time":"2024-02-05T13:02:28Z","timestamp":1707138148000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Altered amyloid-\u03b2 structure markedly reduces gliosis in the brain of mice harboring the Uppsala APP deletion"],"prefix":"10.1186","volume":"12","author":[{"given":"Mar\u00eda","family":"Pagnon de la Vega","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stina","family":"Syv\u00e4nen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vilmantas","family":"Giedraitis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monique","family":"Hooley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evangelos","family":"Konstantinidis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvio R.","family":"Meier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johanna","family":"Rokka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonas","family":"Eriksson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ximena","family":"Aguilar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tara L.","family":"Spires-Jones","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lars","family":"Lannfelt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lars N. 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