Pagnon_2024_Acta.Neuropathol.Commun_12_22

Deposition of amyloid beta (Abeta) 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 Abeta. We recently identified the Uppsala APP mutation (APPUpp), which causes Abeta pathology by a triple mechanism: increased beta-secretase and altered alpha-secretase APP cleavage, leading to increased formation of a unique Abeta 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. Abeta 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 Abeta pathology were studied in cell culture models and mouse brain tissue, using ELISA and immunohistochemistry. Tg-UppSwe mice displayed increased beta-secretase cleavage and suppressed alpha-secretase cleavage, resulting in AbetaUpp42 dominated diffuse plaque pathology appearing from the age of 5-6 months. The gamma-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 Abeta pathology in all models, whereas the Abeta 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 Abeta pathology. The tg-UppSwe mouse model thus recapitulates several pathological features of the Uppsala APP mutation carriers. The presumed unique structural features of AbetaUpp42 aggregates were found to affect their interaction with anti-Abeta antibodies and profoundly modify the Abeta-mediated glial response, which may be important aspects to consider for further development of AD therapies.