Acta neuropathologica communications, 2024-02, Vol.12 (1), p.22-22, Article 22
2024
Volltextzugriff (PDF)
Details
- Autor(en) / Beteiligte
- Titel
- Altered amyloid-β structure markedly reduces gliosis in the brain of mice harboring the Uppsala APP deletion
- Ist Teil von
- Acta neuropathologica communications, 2024-02, Vol.12 (1), p.22-22, Article 22
- Ort / Verlag
- England: BioMed Central
- Erscheinungsjahr
- 2024
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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 [ 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 of AD therapies.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 2051-5960eISSN: 2051-5960DOI: 10.1186/s40478-024-01734-xTitel-ID: cdi_doaj_primary_oai_doaj_org_article_e1e6c9096c0f4e3e9f714a2564198215
- Format
- –
- Schlagworte
- Alzheimer Disease - pathology, Alzheimer's disease (AD), Amyloid beta-Peptides - metabolism, Amyloid beta-Protein Precursor - genetics, Amyloid beta-Protein Precursor - metabolism, Amyloid precursor protein (APP), Amyloid Precursor Protein Secretases - metabolism, Amyloid-beta (A beta), Amyloid-beta (Aβ), Animals, Antibodies, Astrocytes, Brain, Brain - pathology, Disease Models, Animal, FDA approval, Gliosis - pathology, Homogenization, Humans, Immunotherapy, Ligands, Mice, Mice, Transgenic, Microglia, Mutation, Pathology, Peptides, PET imaging